BR112015008954B1 - processes for preparing an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, for preparing at least 9 consecutive batches thereof and for preparing a pharmaceutical composition - Google Patents

Abstract

ALKYLATED CYCLODEXTRIN COMPOSITIONS AND PROCESSES FOR THE PREPARATION AND USE OF THE SAME. The present invention Patent for relates to low chloride alkylated cyclodextrin compositions, together with processes for preparing and using them. The processes of the present invention provide alkylated cyclodextrins with low levels of drug and chloride degrading agents.

Description

CROSS REFERENCE TO RELATED REQUESTS

[001] This claim claims the benefit of United States Provisional Claims Nos. 61 / 716,819, filed on October 22, 2012, and 61 / 871,234, filed on August 28, 2013, both of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION Field of the Invention

[002] The present invention relates to compositions comprising low chloride alkylated cyclodextrin compositions, and processes for the preparation and use thereof. Background of the Invention

[003] Hydrophobic, hydrophilic, polymerized, ionized, non-ionized cyclodextrin derivatives and many other cyclodextrin derivatives have been developed, and their use in various industries has been established. In general, cyclodextrin derivatization proceeds via reactions in which -OH groups in the 2-, 3-, and / or 6- position of the amylose rings of a cyclodextrin are replaced with substituent groups. Substituents include neutral, anionic and / or cationic functional groups.

[004] Known cyclodextrin derivatives, such as alkylated cyclodextrins include, but are not limited to, sulfoalkyl ether cyclodextrins, alkyl ether cyclodextrins (e.g., methyl, ethyl and propyl ether cyclodextrins), hydroxyalkyl cyclodextrins, cyclodextrins, cyclodextrins, cyclodextrins, cyclodextrins, cyclodextrins, cyclodextrins (e.g., succinyl-β-cyclodextrin, and the like), sulfated cyclodextrins, and the like. Alkylated cyclodextrins having more than one type of functional group are also known, such as sulfoalkyl ether-alkyl ether-cyclodextrins (see, for example, WO 2005/042584 and US 2009/0012042, each of which is therefore incorporated by reference in its entirety). In particular, alkylated cyclodextrins having 2-hydroxypropyl groups and / or sulfoalkyl ether groups have found use in pharmaceutical formulations.

onde R é (-H)21-n ou ((-CH2)4-SO3-Na+)n, e n é 6 a 7,1.[005] A derivative of β-cyclodextrin sulfobutyl ether ("SBE-P-CD") has been marketed by CyDex Pharmaceuticals, Inc. as CAPTISOL® and ADVASEP®. The anionic substituent sulfobutyl ether improves the aqueous solubility and safety of the original β-cyclodextrin, which can reversibly form complexes with active pharmaceutical agents, thereby increasing the solubility of active pharmaceutical agents and, in some cases, increasing the stability of the agents active pharmaceutical ingredients in the aqueous solution. CAPTISOL® has a chemical structure according to Formula X:

where R is (-H) 21-n or ((-CH2) 4-SO3-Na +) n, and n is 6 to 7.1.

[006] Sulfoalkyl ether derivatized cyclodextrins (such as CAPTISOL®) are prepared using batch methods, as described in, for example, United States Patent Nos. 5,134,127, 5,376,645 and 6,153,746, each of which is thus incorporated by reference in its entirety.

[007] Sulfoalkyl ether cyclodextrins and other derivatized cyclodextrins can also be prepared according to the methods described in the following published patents and patent applications: US 3,426,011, US 3,453,257, US 3,453,259, US 3,459,731, US4,638,058, US4,727.06, US5,019,562, US5,173,481, US 5,183,809, US 5,241,059, US 5,536,826, US 5,594,125, US 5,658,894, US5,710,268, US5,756,284, US5 .760,015, US5,846,954, US 6,407,079, US 7,625,878, US 7,629,331, US 7,635,773, US2009 / 0012042, JP 05001102, and WO 01/40316, as well as in the following non-patent publications: Lammers et al., Reel. Trav. Chim. Pays-Bas 91: 733 (1972); Staerke 25: 167 (1971), Adam et al, J. Med. Chem. 45: 1806 (2002), Qu et al, J. Inclusion Phenom. Macrocyclic Chem. 43: 213 (2002), Tarver et al, Bioorg. Med. Chem. 70: 1819 (2002), Fromming et al, Cyclodextrins in Pharmacy (Kluwer Academic Publishing, Dordrecht, 1994), Modified Cyclodextrins: Scaffolds and Templates for Supramolecular Chemistry (CJ Easton et al. Eds., Imperial College Press, London, UK, 1999), New Trends in Cyclodextrins and Derivatives (Dominique Duchene ed., Editions de Sante, Paris, FR, 1991), Comprehensive Supramolecular Chemistry 3 (Elsevier Science Inc., Tarrytown, NY), the total revelations of which are thus , incorporated by reference.

[008] Impurities present in an alkylated cyclodextrin composition can reduce the life and potency of an active agent composition. Impurities can be removed from an alkylated cyclodextrin composition by exposure to (e.g., mixing with) activated carbon. The treatment of aqueous solutions containing cyclodextrin and suspensions with activated carbon is known. See, for example, United States Patents Nos. 4,738,923, 5,393,880, and 5,569,756. However, there is a continuing need for alkylated cyclodextrin compositions of higher purity.

BRIEF SUMMARY OF THE INVENTION

[009] The present invention provides a process for the preparation of an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, the process comprising: (a) mixing a cyclodextrin with an alkylating agent to form a reaction medium comprising an alkylated cyclodextrin, a or more unwanted components, and one or more drug-degrading impurities; (b) conducting one or more separations to remove the one or more unwanted components from the reaction medium to form a partially purified solution comprising the alkylated cyclodextrin and one or more drug degradation impurities, in which one or more separations they are ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, or dialysis; (c) preparation of a phosphate-free activated carbon having a residual conductivity of 10 μS or less, by a process comprising subjecting the activated carbon to a first carbon washing process comprising adding water, immersing the carbon in water, and draining from water; and (d) treatment of the partially purified solution with phosphate-free activated carbon having a residual conductivity of 10 μS or less, and production of the alkylated cyclodextrin, in which the alkylated cyclodextrin composition has an absorption of less than 0.5 A.U. due to a drug-degrading agent, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the SAE-CD composition per ml of solution in a cell having a trajectory length of 1 cm.

[0010] In some embodiments, the first carbon washing process involves immersing the carbon in water for at least 20 minutes. In some embodiments, the first carbon washing process involves immersing the carbon in water for about 30 minutes.

[0011] In some embodiments, the first carbon washing process comprises adding water in a countercurrent direction.

[0012] In some embodiments, the process additionally comprises the first carbon washing process at least twice.

[0013] In some embodiments, the process additionally comprises, after the first carbon washing process, a second carbon washing process comprising flowing water over the carbon in a co-current direction. In some embodiments, the second carbon washing process comprises the flow of water over carbon in a co-current direction for at least 1 hour. In some embodiments, the second carbon washing process comprises the flow of water over carbon in a co-current direction for about 3 hours.

[0014] In some embodiments, the process additionally comprises testing the residual water conductivity after the second carbon washing process and, if the residual water conductivity is greater than 10 μS, repeating at least one of the first carbon washing process carbon and the second carbon washing process until the residual conductivity of the water is 10 μS, or less.

[0015] In some embodiments, the alkylated cyclodextrin composition comprises less than 0.5% (w / w) of a chloride. In some embodiments, the alkylated cyclodextrin composition comprises less than 0.1% (w / w) of a chloride. In some embodiments, the alkylated cyclodextrin composition further comprises less than 0.05% (w / w) of a chloride.

[0016] Also disclosed is a process for preparing at least 9 consecutive batches of an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, and less than about 0.05% o (w / w) of a chloride, the process for the preparation of each batch comprising: (a) mixing a cyclodextrin with an alkylating agent to form a reaction medium comprising an alkylated cyclodextrin, one or more undesired components, and one or more drug-degrading impurities; (b) conducting one or more separations to remove the one or more unwanted components from the reaction medium to form a partially purified solution comprising the alkylated cyclodextrin and one or more drug degradation impurities, in which one or more separations they are ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, or dialysis; and (c) treating the partially purified solution with a phosphate-free activated carbon having a residual conductivity of 10 μS or less, and production of the alkylated cyclodextrin, in which the alkylated cyclodextrin composition has an absorption of less than 0.5 A.U. due to a drug-degrading agent, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the SAE-CD composition per ml of solution in a cell having a trajectory length of 1 cm.

[0017] In some embodiments, at least 15 consecutive batches are prepared. In some embodiments, at least 20 consecutive batches are prepared. In some embodiments, at least 30 consecutive batches are prepared. In some embodiments, consecutive batches are prepared within a 10-year period. In some embodiments, consecutive batches are prepared within a 5-year period. In some embodiments, consecutive batches are prepared within a 3-year period.

[0018] In some embodiments, the alkylated cyclodextrin composition additionally comprises less than 500 ppm of a phosphate. In some embodiments, the alkylated cyclodextrin composition further comprises less than 125 ppm of a phosphate.

[0019] In some embodiments, the residual conductivity of the phosphate-free activated carbon is 9μS or less. In some embodiments, the residual conductivity of the phosphate-free activated carbon is 8μS or less.

[0020] In some embodiments, the alkylated cyclodextrin composition additionally comprises less than 0.01% (w / w) of a chloride. In some embodiments, the alkylated cyclodextrin composition additionally comprises less than 0.005% (w / w) of a chloride. In some embodiments, the alkylated cyclodextrin composition additionally comprises less than 0.0001% (w / w) of a chloride.

[0021] In some embodiments, the alkylated cyclodextrin composition has an average degree of substitution from 2 to 9. In some embodiments, the alkylated cyclodextrin composition has an average degree of substitution from 4.5 to 7.5. In some embodiments, the alkylated cyclodextrin composition has an average degree of substitution of 6 to 7.5.

[0022] In some embodiments, the alkylated cyclodextrin composition has an absorption of less than 0.2 AU, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution in a cell having a path length of 1 cm. In some embodiments, the absorption is due to a drug-degrading agent.

[0023] In some embodiments, absorption is determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the SAE-CD composition per ml of solution in a cell having a trajectory length of 1 cm.

[0024] In some embodiments, the alkylated cyclodextrin composition has an absorption of less than 1 AU, as determined by UV / vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the composition of alkylated cyclodextrin per ml of solution in a cell having a path length of 1 cm. In some embodiments, the absorption is due to a core-forming agent.

[0025] In some embodiments, the alkylated cyclodextrin composition has an absorption of less than 0.5 AU, as determined by UV / vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution in a cell having a path length of 1 cm. In some embodiments, the absorption is due to a color forming agent.

[0026] In some embodiments, absorption is determined by UV / vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution in a cell having a length trajectory of 1 cm.

[0027] In some embodiments, the phosphate-free activated carbon is washed with a solvent until the eluted solvent has reached residual conductivity. In some embodiments, the phosphate-free activated carbon is washed with water until the eluted water has reached residual conductivity.

no qual p é 4, 5, ou 6, e R1 é independentemente selecionado em cada ocorrência de -OH ou -O-(C2-C6 alquileno)-SO3--T, no qual T é independentemente selecionado em cada ocorrência de cátions farmaceuticamente aceitáveis, provido que pelo menos um R1 é -OH, e pelo menos um R1 é O-(C2-C6 alquileno)-SO3--T. Em algumas concretizações, R1 é independentemente selecionado em cada ocorrência de -OH ou -O-(C4 alquileno)-SO3--T, e -T é Na+ em cada ocorrência. Em algumas concretizações, a SAE-CD é a sulfobutil éter ciclodextrina (SBE-CD).[0028] In some embodiments, the alkylated cyclodextrin is a sulfoalkyl ether cyclodextrin of Formula (II):

in which p is 4, 5, or 6, and R1 is independently selected for each occurrence of -OH or -O- (C2-C6 alkylene) -SO3 - T, in which T is independently selected for each occurrence of pharmaceutically cations acceptable, provided that at least one R1 is -OH, and at least one R1 is O- (C2-C6 alkylene) -SO3 - T. In some embodiments, R1 is independently selected for each occurrence of -OH or -O- (C4 alkylene) -SO3 - T, and -T is Na + for each occurrence. In some embodiments, SAE-CD is sulfobutyl cyclodextrin ether (SBE-CD).

[0029] In some embodiments, the alkylated cyclodextrin is a hydroxyalkyl ether cyclodextrin (HAE-CD). In some embodiments, HAE-CD is a hydroxypropyl ether cyclodextrin (HPE-CD).

[0030] In some embodiments, the alkylated cyclodextrin composition is combined with one or more excipients.

[0031] In some embodiments, the alkylated cyclodextrin composition is combined with an active agent.

[0032] The present invention is also directed to products prepared by the processes described herein.

[0033] Additional embodiments, characteristics, and advantages of the present invention, as well as the composition, structure, and operation of various embodiments of the present invention, are described in detail below with references to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The accompanying drawings, which are incorporated herein and form a part of the specification, illustrate one or more embodiments of the present invention and, together with the description, serve, additionally, to explain the principles of the invention, and to train a technician in the pertinent technique to produce and use the invention. The following drawings are given by way of illustration only, and are therefore not intended to limit the scope of the present invention.

[0035] FIG. 1 provides a graphical representation of a UV / vis scan (190 nm to 400 nm) of solutions containing a SAE-CD composition after a simple carbon treatment, in which the concentration of sulfoalkyl ether cyclodextrin is varied from 1% to 60 % by weight.

[0036] FIG. 2 provides a graphical representation of a UV / vis scan (190 nm to 400 nm) of solutions containing a SAE-CD composition after a second carbon treatment, in which the concentration of sulfoalkyl ether cyclodextrin is varied from 1% to 60 % by weight.

[0037] FIG. 3 provides a graphical representation of a UV / vis scan (190 nm to 400 nm) of a SBE6.6-P-CD solution after thermal and caustic degradation at a temperature of 60 ° C for a period of 0, 24, 72, 96, and 168 hours, to demonstrate degradation of β-cyclodextrin and formation of drug degradation impurities having an absorption at a wavelength of 245 nm to 270 nm, and / or color forming agents having an absorption at a wavelength from 320 nm to 350 nm.

[0038] FIG. 4 provides a graphic representation of a UV scan (190 nm to 400 nm) of a solution containing an SAE-β-CD after exposure to a temperature of 70 ° C for a period of 48 hours, with subsequent treatment with varying amounts of activated carbon.

[0039] FIG. 5 provides a graphical representation of the initial UV / Vis absorption effect of an SBE6,6-β-CD solution in API stability.

[0040] FIG. 6 provides a graphical representation of impurity levels by a process for the preparation of SBE6,6-β-CD in which impurities are measured using a charged aerosol detector.

[0041] FIG. 7 provides a graphical representation of chloride concentration levels by a SBE6,6-β-CD preparation process in which the chloride concentration is measured using a charged aerosol detector.

[0042] FIG. 8 provides a graphical representation of chloride concentration levels for two batches of SBE6,6-β-CD during ultrafiltration, at the end of ultrafiltration processing, 5, 10, and 20 minutes after adding the first activated carbon column, and 5 , 10, and 20 minutes after addition to the second column of activated carbon, as measured using a loaded aerosol detector.

[0043] FIG. 9 provides a graphical representation of the residual chloride level after (a) the first column of activated carbon (small label), and after (b) the second column of activated carbon (large label) measured using ion chromatography, versus the level of residual conductivity (labeled ZIC pHILIC% C1-) of the final product of SBE6.6-β-CD measured using a ZIC pHILIC column using a loaded aerosol detector (Lots Nos. 17CX01.HQ00056 - 17CX01.HQ00064).

[0044] FIG. 10 provides a graphical representation of the sodium chloride concentration (w / w) of SBE6.6-β-CD samples after two cycles of activated carbon treatment where the activated carbon was washed at a constant conductivity level (Lots Nos. 17CX01.HQ00035 - 17CX01.HQ00079) measured using ion chromatography. The detection limit for ion chromatography is 0.05% by weight of chloride.

[0045] FIG. 11 provides a graphical representation of the sodium chloride concentration (w / w) of SBE6.6-β-CD samples after two cycles of activated carbon treatment where the activated carbon was washed using the procedure described in Example 20 (Lots Nos 17CX01.HQ00080-17CX01.HQ00108) measured using ion chromatography. The detection limit for ion chromatography is 0.05% by weight of chloride.

[0046] FIG. 12 provides a graphical representation of the sodium chloride concentration (w / w) of SBE6.6-β-CD samples after two cycles of activated carbon treatment where the activated carbon was washed using the procedure described in Example 22 (Lots Nos 17CX01.HQ00109-17CX02.HQ00005) measured using ion chromatography. The detection limit for ion chromatography is 0.05% by weight of chloride.

DETAILED DESCRIPTION OF THE INVENTION

[0047] The invention includes combinations and sub-combinations of the various aspects and embodiments disclosed herein. Additionally, when a particular feature, structure, or feature is described in conjunction with an embodiment, it is understood that it is within the skill of a person skilled in the art to effect that feature, structure, or feature in conjunction with other embodiments whether or not explicitly described. These and other aspects of this invention will be apparent upon reference to the following detailed description, examples, claims and attached figures.

[0048] As used herein, percentages refer to "% by weight" and / or "w / w" (weight by weight concentration), unless otherwise indicated.

[0049] References to spatial descriptions (for example, "above", "below", "above", "below", "top", "bottom", etc.) made here are for the purpose of description and illustration only , and should be interpreted as not limiting the processes, equipment, compositions and products of any method of the present invention, which can be spatially arranged in any orientation or manner.

Alkylated cyclodextrin

[0050] An "alkylated cyclodextrin composition" is a composition comprising alkylated cyclodextrins having a degree of substitution or an average degree of substitution (ADS) for a specified substituent. An alkylated cyclodextrin composition comprises an alkylated cyclodextrin species distribution that differs in the specified substituent from the degree of individual substitution for each species, in which the specified substituent for each species is the same. As used herein, an "alkylated cyclodextrin composition" is a substantially pharmaceutically inactive composition (i.e., a composition that does not contain a pharmaceutically active agent). For example, a cyclodextrin composition can comprise at least 90% (w / w) cyclodextrin, at least 95% (w / w) cyclodextrin, at least 97% (w / w) cyclodextrin, at least 99% ( w / w) cyclodextrin, at least 99.9% (w / w) cyclodextrin, or at least 99.99% (w / w) cyclodextrin.

[0051] The alkylated cyclodextrin may be a water-soluble alkylated cyclodextrin, which is any alkylated cyclodextrin that exhibits enhanced water solubility over its corresponding non-derivatized cyclodextrin, and having a molecular structure based on a-, β- or Y— cyclodextrin. In some embodiments, a derivatized cyclodextrin prepared by a process of the present invention has a water solubility of 100 mg / ml, or higher, or a water solubility of less than 100 mg / ml.

[0052] Cyclodextrin can be derivatized with neutral, anionic or cationic substituents, at the C2, C3, or C6 positions of the individual saccharides that form the cyclodextrin ring. Suitable water-soluble alkylated cyclodextrins are described herein. The alkylated cyclodextrin can also be a water-insoluble alkylated cyclodextrin, or an alkylated cyclodextrin which has a lower water solubility than its corresponding non-derivatized cyclodextrin.

[0053] As used herein, a "substituent precursor" or "alkylating agent" refers to a compound, reagent, fraction, or substance capable of reacting with an -OH group present in a cyclodextrin. In some embodiments, the derivatized cyclodextrin includes a substituent, such as a sulfoalkyl ether group, an ether group, an alkyl ether group, an alkenyl group, a hydroxyalkyl group, a hydroxyalkenyl ether group, a thioalkyl ether group, an aminoalkyl ether group, a mercapto group, an amino group, an alkylamino group, a carboxyl group, an ester group, a nitro group, a halo group, an aldehyde group, a 2,3-epoxypropyl group, and combinations thereof. In some embodiments, the alkylating agents include an alkyl sultone (e.g., 1,4-butane sultone, 1,5-pentane sultone, 1,3-propane sultone, and the like). An alkylated cyclodextrin is a cyclodextrin in which one or more -OH groups are replaced with an -O-R group, in which the R contains an alkyl moiety. For example, the group -O-R can be an alkyl ether or a sulfoalkyl ether.

[0054] In some embodiments, alkylated cyclodextrins, such as mixed alkylated cyclodextrins ether include, by way of example, those listed in Table 1 below. Table 1.

[0055] After reaction, purification, and / or isolation, the alkylated decyclodextrin composition of the present invention may comprise small amounts (for example, 1% or less, 0.5% or less, 0.1% or less, 0.05 % or less, 0.01% or less, 0.005% or less, 0.001% or less, 0.0005% or less, or 0.0001% or less, by weight) of a cyclodextrin starting material (e.g. cyclodextrin of non-derivatized origin).

[0056] The alkylated cyclodextrin can be present in the form of high purity. See United States Patent No. 7,635,773. In some embodiments, the alkylated cyclodextrin is a high purity SAE-CD composition having a reduced amount of drug degrading agent as compared to known commercial CAPTISOL® batches. The composition optionally has a reduced amount of phosphate, or excludes phosphate entirely, as compared to known commercial batches of CAPTISOL®. The composition also optionally has lower amounts of a color forming agent, as compared to known commercial batches of CAPTISOL®. The SAE-CD Composition can also have reduced amounts of 1,4-butane sultone and 4-hydroxy-butane-l-sulfonic acid as compared to known commercial batches of CAPTISOL®R.

An alkylated cyclodextrin composition of the present invention provides unexpected advantages over other structurally related alkylated cyclodextrin compositions. By "structurally related" it is significant, for example, that the substituent of the alkylated cyclodextrin in the composition is essentially the same as the substituent of the other alkylated cyclodextrin to which it is being compared. Exemplary advantages may include enhanced purity, reduced content of pyrogens, reduced content of drug-degrading components, reduced content of color-forming agents, reduced content of unreacted substituent precursor, and / or reduced content of starting material unreacted cyclodextrin. An exemplary advantage also includes a reduced chloride content.

no qual: n é 4, 5 ou 6; no qual R1,R2,R3,R4,R5,R6,R7,R8e R9 sãoindependentemente-H, um grupo C1-C8-(alquileno)-SO3- de cadeia reta ou ramificado, ou um grupo C1-C6 opcionalmente substituído de cadeia reta ou ramificado; no qual pelo menos um de R1, R2, R3, R4, R5, R6, R7,R8 e R9 é um grupo C1-C8-(alquileno)-S03- de cadeia reta ou ramificado.[0058] A water-soluble alkylated cyclodextrin composition may comprise a sulfoalkyl ether cyclodextrin compound (SAE-CD), or mixture of compounds, of Formula I:

where: n is 4, 5 or 6; in which R1, R2, R3, R4, R5, R6, R7, R8 and R9 are independently H, a straight or branched C1-C8- (alkylene) -SO3- group, or an optionally substituted C1-C6 group straight or branched; in which at least one of R1, R2, R3, R4, R5, R6, R7, R8 and R9 is a straight or branched C1-C8- (alkylene) -S03- group.

no qual: p é 4, 5 ou 6;[0059] In some embodiments, the SAE-CD Composition comprises the water-soluble alkylated cyclodextrin of Formula II:

where: p is 4, 5 or 6;

[0060] R1 is independently selected on each occurrence of -OH or -SAE-T;

[0061] -SAE- is a -O- (C2-C6 alkylene) -SO3- group, in which at least one SAE is independently an -O- (C2-C6 alkylene) - SO3- group, a -O- group (CH2) gSO3-, in which g is 2 to 6, or 2 to 4, (for example, -OCH2CH2CH2SO3-or-OCH2CH2CH2CH2SO3 -); and -T is independently selected at each occurrence from the group consisting of pharmaceutically acceptable cations , whose group includes, for example, H +, alkali metals (for example, Li +, Na +, K +), alkaline earth metals (for example, Ca + 2, Mg + 2), ammonium ions and amine cations, such as cations of (C1-C6) -alkylamines, piperidine, pyrazine, (C1-C6) -alkanolamine, ethylenediamine, and (C4-C8) - cycloalkanolamine, among others; provided that at least one R1 is a hydroxyl moiety, and at least one R1 is -SAE-T.

[0062] When at least one R1 of a derivatized cyclodextrin molecule is -SAE-T, the degree of substitution, in terms of the -SAE-T fraction, is understood to be at least one (1). When the term -SAE- is used to denote a fraction of sulfoalkyl- (alkylsulfonic acid) -ether, it is understood that the fraction of -SAE- comprises a cation (-T), unless otherwise specified. Accordingly, the terms "SAE" and "-SAE-T" can, as appropriate, be used interchangeably here.

[0063] Since SAE-CD is a polyanionic cyclodextrin, it can be supplied in different salt forms. Suitable counterions include cationic organic atoms, or molecules, and cationic inorganic atoms, or molecules. SAE-CD can include a single type of counterion, or a mix of different counterions. The properties of SAE-CD can be modified by changing the identity of the counterion present. For example, a first salt form of an SAE-CD composition may have greater osmotic potential or greater water activity, reduced energy, than a second salt form other than the same SAE-CD.

[0064] In some embodiments, a sulfoalkyl ether cyclodextrin is complexed with one or more pharmaceutically acceptable cations selected from, for example, H +, alkali metals (for example, Li +, Na +, K +), alkaline earth metals (for example, Ca + 2, Mg + 2), ammonium ions and amine cations, such as (C1-C6) alkylamines, piperidine, pyrazine, (C1-C6) -alkanolamine, ethylenediamine and (C4-C8 cycloalkanolamine, and the like), and the like, and combinations of these.

no qual x denota o grau médio de substituição. Em algumas concretizações, as ciclodextrinas alquilatadas são formadas como sais.[0065] Additional examples of sulfoalkyl ether (SAE) -CD include: Table 2.

where x denotes the average degree of substitution. In some embodiments, the alkylated cyclodextrins are formed as salts.

[0066] Various embodiments of a sulfoalkyl ether cyclodextrin include eicosa-O- (methyl) -6G-O- (4-sulfobutyl) -β-cyclodextrin, heptakis- O- (sulfomethyl) -tetradecakis-O- (3-sulfopropyl) -β-cyclodextrin, heptakis- O - [(1,1-dimethylethyl) dimethylsilyl] -tetradecakis-O- (3-sulfopropyl) -β-cyclodextrin, heptakis-O- (sulfomethyl) -tetradecakis-O- (3-sulfopropyl ) -β- cyclodextrin, and heptakis-O - [(1,1-dimethylethyl) dimethylsilyl] -tetradecakis-O- (sulfomethyl) -β-cyclodextrin. Other known alkylated cyclodextrins containing a sulfoalkyl moiety include sulfoalkylthio and sulfoalkylthioalkyl ether derivatives, such as octakis- (S-sulfopropyl) - octatio-Y-cyclodextrin, octakis-O- [3 - [(2-sulfoethyl) thio] propyl] -β-cyclodextrin], and octakis-S- (2-sulfoethyl) -octathio-Y — cyclodextrin.

[0067] In some embodiments, an alkylated decyclodextrin composition of the present invention is a sulfoalkyl ether cyclodextrin composition — and having an ADS of 2 to 9, 4 to 8, 4 to 7.5, 4 to 7, 4 to 6, 5, 4.5 to 8, 4.5 to 7.5, 4.5 to 7, 5 to 8, 5 to 7.5, 5 to 7, 5.5 to 8, 5.5 to 7.5, 5.5 to 7, 5.5 to 6.5, 6 to 8, 6 to 7.5, 6 to 7.1, 6.5 to 7.1, 6.2 to 6.9, or 6.5 , by alkylated cyclodextrin, and the remaining substituents are -H.

no qual n é 4, 5 ou 6, no qual R1,R2,R3,R4,R5,R6,R7,R8eR9sãoindependentemente selecionados de: -H, um grupo C1-C8-(alquileno)- S03- de cadeia reta ou ramificado, e um grupo C1-C6 opcionalmente substituído de cadeia reta ou ramificado.[0068] In some embodiments, the alkylated cyclodextrin is a compound of Formula III:

in which n is 4, 5 or 6, in which R1, R2, R3, R4, R5, R6, R7, R8 and R9 are independently selected from: -H, a straight or branched C1-C8- (alkylene) group - S03- , and an optionally substituted straight or branched C1-C6 group.

no qual: m é 4, 5 ou 6; R é independentemente selecionado em cada ocorrência a partir do grupo consisting de -OH e AE; e AE é -O-(C1- C6alquil); provido que pelo menos um R é -OH; e pelo menos um AE está presente. Derivados de AE-CD exemplares adicionais incluem: Tabela 3.

no qual ME denota metil éter, EE denota etil éter, PE denota propil éter, BE denota butil éter, PtE denota pentil etil, HE denota hexil éter, e y denota o grau médio de substituição.[0069] A water-soluble alkylated cyclodextrin composition can comprise an alkyl ether (AE) -cyclodextrin compound, or mixture of compounds, of Formula IV:

where: m is 4, 5 or 6; R is independently selected at each occurrence from the group consisting of -OH and AE; and AE is -O- (C1- C6alkyl); provided that at least one R is -OH; and at least one AE is present. Additional exemplary AE-CD derivatives include: Table 3.

in which ME denotes methyl ether, EE denotes ethyl ether, PE denotes propyl ether, BE denotes butyl ether, PtE denotes pentyl ethyl, HE denotes hexyl ether, and y denotes the average degree of substitution.

no qual: "v" é 4, 5 ou 6; "Q" é independentemente selecionado em cada ocorrência a partir do grupo consistindo de -OH, e -HAE; e HAE é HO(C1-C6 alquil)-O-, provido que pelo menos uma fração de -HAE está presente.[0070] A water-soluble alkylated cyclodextrin composition may comprise a HAE-cyclodextrin compound, or mixture of compounds, of Formula V:

where: "v" is 4, 5 or 6; "Q" is independently selected on each occurrence from the group consisting of -OH, and -HAE; and HAE is HO (C1-C6 alkyl) -O-, provided that at least a fraction of -HAE is present.

no qual HME denota hidroximetil éter, HEE denota hidroxietil éter, HPE denota hidroxipropil éter, HBE denota hidroxibutil éter, HPtE denota hidroxipentil éter, HHE denota hidroxihexil éter, e z denota o grau médio de substituição.[0071] Additional exemplary hydroxyalkyl ether (HAE) -CD derivatives include: Table 4.

in which HME denotes hydroxymethyl ether, HEE denotes hydroxyethyl ether, HPE denotes hydroxypropyl ether, HBE denotes hydroxybutyl ether, HPtE denotes hydroxypentyl ether, HHE denotes hydroxyhexyl ether, ez denotes the average degree of substitution.

no qual: "v" é 4, 5 ou 6; "A" é independentemente selecionado em cada ocorrência a partir do grupo consistindo de -OH, -SAET e -AE; x é o grau de substituição para a fração de SAET, e é 1 a 3v + 5; y é o grau de substituição para a fração de AE, e é 1 a 3v + 5; -SAE é -O-(C2-C6 alquileno)-S03-; T é independentemente em cada ocorrência um cátion; e AE é -O(C1-C3 alquil); provido que pelo menos uma fração de -SAET e pelo menos uma fração de -AE estão presentes; e a soma de x, y e o número total de grupos -OH em uma ciclodextrina alquilatada, é 3v + 6.[0072] A water-soluble alkylated cyclodextrin composition may comprise a SAE-AE-CD compound, or mixture of compounds, of Formula VI:

where: "v" is 4, 5 or 6; "A" is independently selected on each occurrence from the group consisting of -OH, -SAET and -AE; x is the degree of substitution for the SAET fraction, and is 1 to 3v + 5; y is the degree of substitution for the fraction of AE, and is 1 to 3v + 5; -SAE is -O- (C2-C6 alkylene) -S03-; T is independently a cation at each occurrence; and AE is -O (C1-C3 alkyl); provided that at least a fraction of -SAET and at least a fraction of -AE are present; and the sum of x, y and the total number of -OH groups in an alkylated cyclodextrin, is 3v + 6.

[0073] Specific embodiments of the derivatives of the present invention include those in which: 1) the alkylene fraction of the SAE has the same number of carbons as the alkyl fraction of the AE; 2) the alkylene fraction of the SAE has a different number of carbons than the alkyl fraction of the AE; 3) the alkyl and alkylene fractions are independently selected from the group consisting of a straight or branched chain fraction; 4) the alkyl and alkylene fractions are independently selected from the group consisting of a saturated or unsaturated fraction; 5) the ADS for the SAE group is greater than or close to the ADS for the AE group; or 6) the ADS for the SAE group is less than the ADS for the AE group.

no qual: "v" é 4, 5 ou 6; "X" é independentemente selecionado em cada ocorrência a partir do grupo consistindo de -OH, SAET e HAE; x é o grau de substituição para a fração de SAET, e é 1 a 3w + 5; y é o grau de substituição para a fração de HAE, e é 1 a 3w + 5; -SAE é -O-(C2-C6 alquileno)-S03-; T é independentemente em cada ocorrência um cátion; e HAE é HO-(C1-C6 alquil)-O-; provido que pelo menos uma fração de - SAET e pelo menos uma fração de -HAE estão presentes; e a soma de x, y, e o número total de grupos -OH em uma ciclodextrina alquilatada é3w+6.[0074] A water-soluble alkylated cyclodextrin composition can comprise a SAE-HAE-CD compound, or mixture of compounds, of Formula VII:

where: "v" is 4, 5 or 6; "X" is independently selected on each occurrence from the group consisting of -OH, SAET and HAE; x is the degree of substitution for the SAET fraction, and is 1 to 3w + 5; y is the degree of substitution for the HAE fraction, and is 1 to 3w + 5; -SAE is -O- (C2-C6 alkylene) -S03-; T is independently a cation at each occurrence; and HAE is HO- (C1-C6 alkyl) -O-; provided that at least a fraction of - SAET and at least a fraction of -HAE are present; and the sum of x, y, and the total number of -OH groups in an alkylated cyclodextrin is 3w + 6.

[0075] Alkylated cyclodextrin may include SAE-CD, HAE-CD, SAE-HAE-CD, HANE-CD, HAE-AE-CD, HAE-SAE-CD, AE-CD, SAE-AE-CD, neutral cyclodextrin , anionic cyclodextrin, cationic cyclodextrin, halo-derivatized cyclodextrin, amino-derivatized cyclodextrin, nitrile-derivatized cyclodextrin, aldehyde-derivatized cyclodextrin, derivatized, cyclodextrinized, cyclodextrin, derivatized, cyclodextrin, cyclodextrin, cyclodextrin, cyclodextrin, cyclodextrin, cyclodextrin derivatized, or succinyl-derivatized cyclodextrin.

[0076] Within a given alkylated cyclodextrin composition, the substituents of the alkylated cyclodextrin (s) thereof may be the same or different. For example, fractions of SAE or HAE may have the same or different type of alkylene (alkyl) radical after each occurrence in an alkylated cyclodextrin composition. In such embodiments, the alkylene radical in the SAE or HAE fraction can be ethyl, propyl, butyl, pentyl or hexyl, at each occurrence in an alkylated cyclodextrin composition.

[0077] Alkylated cyclodextrins may differ in their degree of substitution by functional groups, the number of carbons in the functional groups, their molecular weight, the number of glucopyranose units contained in the base cyclodextrin used to form the derivatized cyclodextrin, and or its patterns of replacement. In addition, derivatization of a cyclodextrin with functional groups occurs in a controlled, though not exact, manner. For this reason, the degree of substitution is actually a number that represents the average number of functional groups per cyclodextrin (for example, SBE7-β-CD has an average of 7 substitutions per cyclodextrin). Thus, it has an average degree of substitution ("ADS") of 7. In addition, the substitution regiochemistry of the hydroxyl groups of the cyclodextrin is variable with respect to the replacement of specific hydroxyl groups of the hexose ring. For this reason, the substitution of the different hydroxyl groups is similarly to occur during the production of the derivatized cyclodextrin, and a particular derivatized cyclodextrin will have a preferred substitution pattern, although a non-exclusive or specific substitution pattern. Given the above, the molecular weight of a particular derivatized cyclodextrin composition can vary from batch to batch.

[0078] In a cyclodextrin molecule of simple origin, there are 3v + 6 fractions of hydroxyl available for derivatization. Where v = 4 (α-cyclodextrin), "y" the degree of substitution for the fraction can vary in value from 1 to 18. Where v = 5 (β-cyclodextrin), "y" the degree of substitution for the fraction can vary in value from 1 to 21. Where v = 6 (Y-cyclodextrin), "y" the degree of substitution for the fraction can vary in value from 1 to 24. In general, "y" also varies in value from 1 to 3v + g, where g varies in value from 0 to 5. In some embodiments, "y" ranges from 1 to 2v + g, or from 1 to lv + g.

[0079] The degree of substitution ("DS") for a specific fraction (SAE, HAE or AE, for example) is a measure of the number of SAE substituents (HAE or AE) attached to an individual cyclodextrin molecule, in other words, the moles of substituent per mole of cyclodextrin. Therefore, each substituent has its own DS for an individual alkylated cyclodextrin species. The average degree of substitution ("ADS") for a substituent is a measure of the total number of substituents present per cyclodextrin molecule for the delivery of alkylated cyclodextrins within an alkylated cyclodextrin composition of the present invention. Therefore, SAE4-CD has an ADS (per molecule of CD) of 4.

Some embodiments of the present invention include those in which: 1) more than half of the alkylated cyclodextrin hydroxyl fractions are derivatized; 2) half or less than half of the hydroxyl fractions of the alkylated cyclodextrin are derivatized; 3) the alkylated cyclodextrin substituents are the same after each occurrence; 4) the alkylated cyclodextrin substituents comprise at least two different substituents; or 5) the alkylated cyclodextrin substituents comprise one or more of the substituents selected from the group consisting of unsubstituted alkyl, substituted alkyl, halide (halo), haloalkyl, amine (amino), aminoalkyl, aldehyde, carbonylalkyl, nitrile, cyanoalkyl, sulfoalkyl, hydroxyalkyl, carboxyalkyl, thioalkyl, unsubstituted alkylene, substituted alkylene, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0081] The alkylated cyclodextrin compositions may comprise individual plural species of alkylated cyclodextrin that differ in degree of individual substitution, such that the average degree of substitution is calculated, as described herein, from individual degrees of species substitution. More specifically, a SAE-CD derivative composition can comprise plural species of SAE-CD, each having a specific degree of individual substitution with respect to the SAE substituent. As a consequence, the ADS for SAE of an SAE-CD derivative composition represents an average of the IDS values of the population of individual molecules in the composition. For example, a SAE5.2-CD composition comprises a distribution of plural SAEX-CD molecules, in which "x" (the DS for SAE groups) can range from 1 to 10-11 for individual cyclodextrin molecules; however, the population of SAE cyclodextrin molecules is such that the average value for "x" (the ADS for SAE groups) is 5.2.

[0082] The alkylated cyclodextrin compositions can have a high to moderate to low ADS.

[0083] The alkylated cyclodextrin compositions can also have a wide or narrow "span", which is the number of individual DS species within an alkylated cyclodextrin composition. For example, an alkylated cyclodextrin composition comprising a unique alkylated cyclodextrin species having a single specified individual DS is said to have an extension of one, and the individual alkylated cyclodextrin DS equals the ADS of its alkylated cyclodextrin composition. An electropherogram, for example, of an alkylated cyclodextrin with an extension of one, must have only one species of alkylated cyclodextrin with respect to the DS. An alkylated cyclodextrin composition having an extension of two comprises two individual species of cyclodextrinalkylated which differ from their individual DS, and their electropherogram, for example, would indicate two different species of cyclodextrinalkylated which differ from DS. three individual species of alkylated cyclodextrin that differ in their individual DS. The length of an alkylated cyclodextrin composition typically ranges from 5 to 15, or 7 to 12, or 8 to 11.

[0084] A parent cyclodextrin includes a hydroxyl second group at the C-2 and C-3 positions of the glucopyranose residues that form the cyclodextrin, and a primary hydroxyl at the C-6 position thereof. Each of these hydroxyl fractions is available for derivatization by substituent precursor. Depending on the synthetic methodology employed, the substituent fractions can be randomly distributed, or in a somewhat orderly manner among the available hydroxyl positions. The regioisomerism of the derivatization by the substituent can also be varied as desired. The regioisomerism of each composition is independently selected. For example, most of the substituents present can be located on a primary hydroxyl group, or on one or both of the secondary hydroxyl groups of the parent cyclodextrin. In some embodiments, the primary distribution of the substituents is C-3> C-2> C-6, while in other embodiments, the primary distribution of the substituents is C-2> C-3> C-6. Some embodiments of the present invention include an alkylated cyclodextrin molecule in which a minority of the substituent fractions are located at the C-6 position, and a majority of the substituent fractions are located at the C-2 and / or C-3 position. Still other embodiments of the present invention include an alkylated cyclodextrin molecule in which the substituent fractions are substantially uniformly distributed between the C-2, C3, and C-6 positions.

An alkylated cyclodextrin composition comprises a distribution of individual plural species of alkylated cyclodextrin, each species having an individual degree of substitution ("IDS"). The content of each species of cyclodextrin in a particular composition can be quantified using capillary electrophoresis. The method of analysis (capillary electrophoresis, for example, for charged alkylated cyclodextrins) is sufficiently sensitive to distinguish between the compositions having only 5% of an alkylated cyclodextrin and 95% of another alkylated cyclodextrin from starting alkylated cyclodextrin compositions.

[0086] The aforementioned variations between the individual species of alkylated cyclodextrins in a distribution, can lead to changes in the complexation equilibrium constant Ki: i which, in turn, will affect the required molar ratios of the derivatized cyclodextrin for active agent. The equilibrium constant is also somewhat variable with temperature, and subsidies on the ratio are required, such that the agent remains solubilized during the temperature fluctuations that can occur during production, storage, transportation, and use. The equilibrium constant can also vary with pH, and allowances in the ratio may be required, such that the agent remains solubilized during the pH fluctuations that can occur during production, storage, transportation, and use. The equilibrium constant can also vary due to the presence of other excipients (for example, buffers, preservatives, antioxidants). Consequently, the ratio of derivatized cyclodextrin to active agent can be varied from the reasons given here in order to compensate for the variables mentioned above. .

[0087] Alkylated cyclodextrins produced according to the process of the present invention can be used in compositions, formulations, methods and systems, such as those disclosed in United States Patent Nos. 5,134,127, 5,376,645.5,914.122,5,874,418,6,046,177,6,133,248,6,153,746, 6,407,079, 6,869,939, 7,034,013, 7,625,878, 7,629,331, and 7,635 .773; United States Publications Nos. 2005/0164986, 2005/0186267, 2005 / 0250738,2006 / 0258537,2007 / 0020196,2007 / 0020298, 2007 / 0020299,2007 / 0175472,2007 / 0202054,2008 / 0194519, 2009/0011037, 2009/0012042, 2009 /001 0123540; United States Order Nos. 12 / 404,174.12 / 407,734.61 / 050,918.61 / 177,718, and 61 / 182,560; and PCT International Orders Nos. PCT / US06 / 62346, total disclosures of the quaios are hereby incorporated by reference. The alkylated cyclodextrins prepared according to the processes herein can also be used as suitable substitutes for other known grades of alkylated cyclodextrins having the same functional groups.

[0088] In some embodiments, an alkylated cyclodextrin has greater solubility in water than a corresponding cyclodextrin from which an alkylated cyclodextrin composition of the present invention is prepared. For example, in some embodiments, a non-derivatized cyclodextrin is used as a starting material, for example, a-, β- or Y — cyclodextrin, commercially available from, for example, WACKER BIOCHEM CORP. (Adrian, MI), and other sources. Non-derivatized cyclodextrins have limited water solubility compared to the alkylated cyclodextrin compositions of the present invention. For example, derivatized α-CD, β-CD, Y-CD have a solubility in water of about 145 g / L, 18.5 g / L, and 232 g / L, respectively, in saturation.

[0089] The water-soluble alkylated cyclodextrin composition is optionally processed to remove a larger portion (for example,> 50%) of a non-derivatized cyclodextrin, or other contaminants.

[0090] The terms "alkylene" and "alkyl" as used herein (for example, in the -O- (C2-C6-alkylene) S03- group, or in the alkylamine cations), include linear, cyclic, divalent alkylene groups and branched, saturated and unsaturated (i.e., containing one or more double bonds), and monovalent alkyl groups, respectively. For example, the SAE or HAE fractions may have the same or different type of alkylene (alkyl) radical after each occurrence in an alkylated cyclodextrin composition. In such embodiments, the alkylene radical in the SAE or HAE fraction can be ethyl, propyl, butyl, pentyl or hexyl at each occurrence in an alkylated cyclodextrin composition.

[0091] The term "alkanol" in this text, likewise, includes both linear, cyclic and branched, saturated and unsaturated alkyl components of the alkanol groups, where the hydroxyl groups can be located at any position in the alkyl fraction . The term "cycloalkanol" includes cyclic alcohols that are unsubstituted or substituted (for example, by methyl or ethyl).

[0092] In some embodiments, the present invention provides a cyclodextrin alkyl ether (AE-CD) composition, comprising a cyclodextrin alkyl ether having an average degree of substitution of 2 to 9, less than 500 ppm of a phosphate, and less than 0.5% (w / w) of a chloride, in which the AE-CD composition has an absorption of less than 1 AU, as determined by UV / vis spectrophotometry at a wavelength of 245 nm at 270 nm for an aqueous solution containing 300 mg of the AE-CD composition per ml of solution in a cell having a path length of 1 cm. In some embodiments, said absorption of 1 A.U. or less is due to a drug-degrading agent. In some embodiments, the alkyl ether cyclodextrin composition is not a sulfobutyl ether cyclodextrin composition. In some embodiments, the cyclodextrin alkyl ether is not a β-cyclodextrin sulfobutyl ether. In some embodiments, the AE-CD composition has an absorption of 0.5 A.U. or less, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the AE-CD composition per ml of solution in a cell having a path length of 1 cm . In some embodiments, said absorption of 0.5 A.U. or less is due to a drug-degrading agent. In some embodiments, the AE-CD composition has an absorption of 0.2 A.U. or less, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the AE-CD composition per ml of solution in a cell having a path length of 1 cm . In some embodiments, said absorption of 0.2 A.U. or less is due to a drug-degrading agent. In some embodiments, the absorption of the AE-CD composition is determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the AE-CD composition per ml of solution in a cell having a path length of 1 cm.

[0093] In some embodiments, the present invention provides a cyclodextrin alkyl ether (AE-CD) composition, comprising a cyclodextrin alkyl ether having an average degree of substitution of 2 to 9, less than 500 ppm of a phosphate, and less than 0.5% (w / w) of a chloride, in which the AE-CD composition has an absorption of less than 1 AU, as determined by UV / vis spectrophotometry at a wavelength of 320 nm at 350 nm for an aqueous solution containing 300 mg of the AE-CD composition per ml of solution in a cell having a path length of 1 cm. In some embodiments, said absorption of less than 1 A.U. it is due to a heat forming agent. In some embodiments, the alkyl ether cyclodextrin composition is not a sulfobutyl ether cyclodextrin composition. In some embodiments, the cyclodextrin alkyl ether is not a β-cyclodextrin sulfobutyl ether. In some embodiments, the AE-CD composition has an absorption of 0.5 A.U. or less, as determined by UV / vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the AE-CD composition per ml of solution in a cell having a path length of 1 cm . In some embodiments, said absorption of 0.5 A.U. or less is due to a heat forming agent. In some embodiments, the AE-CD composition has an absorption of 0.2 A.U. or less, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the AE-CD composition per ml of solution in a cell having a path length of 1 cm . In some embodiments, said absorption of 0.2 A.U. or less is due to a drug-degrading agent. In some embodiments, the absorption of the AE-CD composition is determined by UV / vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the SAE-CD composition per ml of solution in a cell having a path length of 1 cm.

[0094] In some embodiments, the average degree of substitution for the AE-CD is 4.5 to 7.5. In some embodiments, the average degree of substitution for the AE-CD is 6 to 7.5. In some embodiments, the average degree of substitution for the AE-CD is 6.2 to 6.9.

[0095] In some embodiments, the present invention provides a composition comprising an AE-CD composition and an active agent.

[0096] In some embodiments, the present invention provides a composition of sulfoalkyl ether cyclodextrin (SAE-CD), comprising a sulfoalkyl ether cyclodextrin having an average degree of substitution of 2 to 9, less than 500 ppm of a phosphate, and less than 0.5% (w / w) of a chloride, in which the SAE-CD composition has an absorption of less than 1 AU, as determined by UV / vis spectrophotometry at a wavelength of 245 nm at 270 nm for an aqueous solution containing 300 mg of the SAE-CD composition per ml of solution in a cell having a path length of 1 cm. In some embodiments, said absorption of less than 1 A.U. it is due to a drug-degrading agent. In some embodiments, the sulfoalkyl ether cyclodextrin composition is not a sulfobutyl ether cyclodextrin composition. In some embodiments, sulfoalkyl ether cyclodextrin is not a sulfobutyl β-cyclodextrin ether. In some embodiments, the SAE-CD composition has an absorption of 0.5 A.U. or less, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the SAE-CD composition per ml of solution in a cell having a path length of 1 cm . In some embodiments, said absorption of 0.5 A.U. or less is due to a drug-degrading agent. In some embodiments, the SAE-CD composition has an absorption of 0.2 A.U. or less, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the SAE-CD composition per ml of solution in a cell having a path length of 1 cm . In some embodiments, said absorption of 0.2 A.U. or less is due to a drug-degrading agent. In some embodiments, the absorption of the SAE-CD composition is determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the SAE-CD composition per ml of solution in a cell having a path length of 1 cm.

no qual p é 4, 5, ou 6, e R1 é independentemente selecionado em cada ocorrência de -OH, ou -O-(C2-C6 alquileno)-SO3 -T, no qual T é independentemente selecionado em cada ocorrência de cátions farmaceuticamente aceitáveis, provido que pelo menos um R1 é -OH, e pelo menos um R1 é O-(C2-C6 alquileno)-S03-T. Em algumas concretizações, R1 é independentemente selecionado em cada ocorrência de -OH, ou -O-(C4 alquileno)-SO3 -T, e -T é Na+ em cada ocorrência.[0097] In some embodiments, sulfoalkyl ether cyclodextrin is a compound of Formula (II):

in which p is 4, 5, or 6, and R1 is independently selected for each occurrence of -OH, or -O- (C2-C6 alkylene) -SO3 -T, in which T is independently selected for each occurrence of pharmaceutically cations acceptable, provided that at least one R1 is -OH, and at least one R1 is O- (C2-C6 alkylene) -S03-T. In some embodiments, R1 is independently selected at each occurrence of -OH, or -O- (C4 alkylene) -SO3 -T, and -T is Na + at each occurrence.

[0098] In some embodiments, the present invention provides a composition of sulfoalkyl ether cyclodextrin (SAE-CD), comprising a sulfoalkyl ether cyclodextrin having an average degree of substitution of 2 to 9, less than 500 ppm of a phosphate, and less than 0.5% (w / w) of a chloride, in which the SAE-CD composition has an absorption of 1 AU or less, as determined by UV / vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the SAE-CD composition per ml of solution in a cell having a path length of 1 cm . In some embodiments, said absorption of 1 A.U. or less is due to a heat forming agent. In some embodiments, the sulfoalkyl ether cyclodextrin composition is not a sulfobutyl ether cyclodextrin composition. In some embodiments, sulfoalkyl ether cyclodextrin is not a sulfobutyl β-cyclodextrin ether. In some embodiments, the SAE-CD composition has an absorption of 0.5 A.U. or less, as determined by UV / vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the SAE-CD composition per ml of solution in a cell having a path length of 1 cm . In some embodiments, said absorption of 0.5 A.U. or less is due to a heat forming agent. In some embodiments, the SAE-CD composition has an absorption of 0.2 A.U. or less, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the SAE-CD composition per ml of solution in a cell having a path length of 1 cm . In some embodiments, said absorption of 0.2 A.U. or less is due to a heat forming agent. In some embodiments, the absorption of the SAE-CD composition is determined by UV / vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the SAE-CD composition per ml of solution in a cell having a path length of 1 cm.

[0099] In some embodiments, the average degree of substitution for SAE-CD is 4.5 to 7.5. In some embodiments, the average degree of substitution for SAE-CD is 6 to 7.5. In some embodiments, the average degree of substitution for SAE-CD is 6.2 to 6.9.

[00100] In some embodiments, the present invention provides a composition comprising a SAE-CD composition and an active agent.

[00101] The present invention is also directed to a method for stabilizing an active agent, the method comprising providing an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, less than 500 ppm of a phosphate, and less than 0.5% of a chloride, in which the alkylated cyclodextrin composition has an absorption of less than 1 AU, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the composition of alkylated cyclodextrin per ml of solution in a cell having a path length of 1 cm; and combining the alkylated cyclodextrin composition with an active agent. In some embodiments, said absorption of less than 1 A.U. it is due to a drug-degrading agent.

[00102] The present invention is also directed to a method for stabilizing an active agent, the method comprising providing an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, less than 500 ppm of a phosphate, and less than 0.5% of a chloride, in which the alkylated cyclodextrin composition has an absorption of less than 1 AU, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the composition of alkylated cyclodextrin per ml of solution in a cell having a path length of 1 cm; and combining the alkylated cyclodextrin composition with an active agent. In some embodiments, said absorption of less than 1 A.U. it is due to a heat forming agent. The present invention provides a process for the preparation of an alkylated cyclodextrin composition, the process comprising:

[00103] (a) mixing a cyclodextrin with an alkylating agent in the presence of an alkalinizing agent to form a reaction medium comprising an alkylated cyclodextrin, one or more unwanted components, and one or more drug-degrading impurities;

[00104] (b) conducting one or more separations to remove the one or more unwanted components from the reaction medium to form a partially purified solution comprising alkylated cyclodextrin, and one or more drug degradation impurities, in which the one or more separations are ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, or dialysis;

[00105] (c) treating the partially purified solution with a phosphate-free activated carbon having a conductivity of 10 μS or less, and producing the alkylated cyclodextrin.

[00106] The term "batch" or "batch", as used herein, refers to a processing or production course distinct from the beginning of the processing course to the end of the processing cycle. In some embodiments, the present invention provides a process for preparing more than one batch of an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, the process comprising: (a) mixing a cyclodextrin with an alkylating agent to form a means of reaction comprising an alkylated cyclodextrin, one or more unwanted components, and one or more drug-degrading impurities; (b) conducting one or more separations to remove the one or more unwanted components from the reaction medium to form a partially purified solution comprising the alkylated cyclodextrin and one or more drug degradation impurities, in which one or more separations they are ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, or dialysis; (c) treating the partially purified solution with a phosphate-free activated carbon having a residual conductivity of 10 μS or less, and producing a batch of an alkylated cyclodextrin; and (d) repeat (a) - (c) to obtain another batch of an alkylated cyclodextrin composition.

[00107] In some embodiments, more than one batch of an alkylated cyclodextrin composition is at least 4 batches, at least 5 batches, at least 6 batches, at least 7 batches, at least 8 batches, at least 9 batches, at least 10 batches, at least 11 batches, at least 12 batches, at least 13 batches, at least 15 batches, at least 16 batches, at least 17 batches, at least 18 batches, at least 19 batches, at least 20 lots, at least 30 lots, at least 40 lots, at least 50 lots, at least 60 lots, at least 70 lots, at least 80 lots, at least 90 lots, or at least 100 lots. In some embodiments, more than one batch of an alkylated cyclodextrin composition is at least 3 batches. In some embodiments, more than one batch of an alkylated cyclodextrin composition is 4 to 100 batches, 10 to 100 batches, 20 to 100 batches, 30 to 100 batches, 40 to 100 batches, 50 to 100 batches, 10 to 20 lots, 10 to 30 lots, 10 to 40 lots, or 10 to 50 lots. In some embodiments, more than one batch of an alkylated cyclodextrin composition is 3 to 100 batches.

[00108] In some embodiments, more than one batch of an alkylated cyclodextrin composition is prepared within a period of 6 months, within a period of 1 year, within a period of 2 years, within a period of 3 years, within a period of 4 years, within a period of 5 years, within a period period of 6 years, within a period of 7 years, within a period of 8 years, within a period of 9 years, within a period of 10 years, within a period of 15 years, or within a period of 20 years.

[00109] In some embodiments, the alkylated cyclodextrin composition is produced in a different course of at least 10 kilos, a different course of at least 50 kilos, a different course of at least 100 kilos, a different course of at least 200 kilos , a different course of at least 300 kilos, a different course of at least 400 kilos, a different course of at least 500 kilos, a different course of at least 600 kilos, a different course of at least 700 kilos, a different course of at least 800 kilos, a different course of at least 900 kilos, a different course of at least 1000 kilos, a different course of at least 1500 kilos, or a different course of at least 2000 kilos.

[00110] In some embodiments, 50% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.1% (w / w), 65% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.1% (w / w), 75% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.1% (w / w), 80% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.1% (w / w), 85% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.1 % (w / w), 90% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.1% (w / w), 95% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.1% (w / w), 98% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.1% (w / w), 50% or more of the make up lots alkylated cyclodextrin composition has a chloride level of less than 0.08% (w / w), 65%> or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.08% (p / w), 75% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.08% (w / w), 80% or more of the batches of the alkylated cyclodextrin composition have a chloride level less than 0.08% (w / w), 85% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.08% (w / w), 90% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.08% (w / w), 95% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.08% (p / w), 98% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.08% (w / w), 50% or more of the batches of the alkylated cyclodextrin composition have a chlor level eto less than 0.05% (w / w), 65% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.05% (w / w), 75% or more of lots of the alkylated cyclodextrin composition have a chloride level of less than 0.05% (w / w), 80% or more of the lots of the alkylated cyclodextrin composition have a chloride level of less than 0.05% ( w / w), 85% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.05% (w / w), 90% or more of the batches of the alkylated cyclodextrin composition have a level of chloride of less than 0.05% (w / w), 95% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.05% (w / w), or 98% or more of the batches of the alkylated cyclodextrin composition have a chloride level of less than 0.05% (w / w).

[00111] In some embodiments, the lots of the alkylated cyclodextrin composition are prepared sequentially.

[00112] In some embodiments, the lots of the alkylated cyclodextrin composition are prepared consecutively. For example, in some embodiments, more than one batch of an alkylated cyclodextrin composition has at least 4 consecutive batches in a series, at least 5 consecutive batches in a series, at least 6 consecutive batches in a series, at least 7 consecutive batches in a series, at least 8 consecutive batches in a series, at least 9 consecutive batches in a series, at least 10 consecutive batches in a series, at least 11 consecutive batches in a series, at least 12 consecutive batches in a series , at least 13 consecutive batches in a series, at least 14 consecutive batches in a series, at least 15 consecutive batches in a series, at least 16 consecutive batches in a series, at least 17 consecutive batches in a series, at least 18 batches consecutive batches in a series, at least 19 consecutive batches in a series, at least 20 consecutive batches in a series, at least 30 consecutive batches in a series, at least 40 consecutive batches in a series , at least 50 consecutive batches in a series, at least 60 consecutive batches in a series, at least 70 consecutive batches in a series, at least 80 consecutive batches in a series, at least 90 consecutive batches in a series, at least 100 batches consecutive in a series. In some embodiments, more than one batch of an alkylated cyclodextrin composition is at least 3 consecutive batches in a series. In some embodiments, more than one batch of an alkylated cyclodextrin composition is 4 to 100 consecutive batches in a series, 10 to 100 consecutive batches in a series, 20 to 100 consecutive batches in a series, 30 to 100 consecutive batches in a series, 40 to 100 consecutive batches in a series, 50 to 100 consecutive batches in a series, 10 to 20 consecutive batches in a series, 10 to 30 consecutive batches in a series, 10 to 40 consecutive batches in a series, or 10 to 50 consecutive batches in a series. In some embodiments, more than one batch of an alkylated cyclodextrin composition is 3 to 100 consecutive batches in a series.

[00113] In some embodiments, more than one consecutive batch in a series of an alkylated cyclodextrin composition is prepared within a period of 6 months, within a period of 1 year, within a period of 2 years, within over a period of 3 years, within a period of 4 years, within a period of 5 years, within a period of 6 years, within a period of 7 years, within a period of 8 years, within a period of 9 years, within a period of 10 years, within a period of 15 years, or within a period of 20 years.

[00114] In some embodiments, 50% or more of the consecutive batches of the alkylated cyclodextrin composition have a chloride level of less than 0.1% (w / w), 65% or more of the consecutive batches of the alkylated cyclodextrin composition have a chloride level of less than 0.1% (w / w), 75% or more of consecutive batches of the alkylated cyclodextrin composition have a less than 0.1% (w / w) chloride level, 80% or more of the consecutive lots alkylated cyclodextrin composition has a level of chloride less than 0.1% (w / w), 85% or more of the consecutive batches of the alkylated cyclodextrin composition has a level of less than 0.1% (w / w), 90% or more consecutive lots of the alkylated cyclodextrin composition have a level of chloride less than 0.1% (w / w), 95% or more of the consecutive lots of the alkylated cyclodextrin composition have a level of less than 0.1% (w / w), 98% or more of the consecutive lots of the alkylated cyclodextrin composition have a chloride level less that 0.1% (w / w), 50% or more of the consecutive lots of the alkylated cyclodextrin composition have a chlorine level of less than 0.08% (w / w), 65% or more of the consecutive lots of the alkylated cyclodextrin composition have a chlorine level of less than 0.08 % (w / w), 75% or more of the consecutive batches of the alkylated cyclodextrin composition have a chlorine level of less than 0.08% (w / w), 80% or more of the consecutive batches of the alkylated cyclodextrin composition have a chlorine level of less than 0.08% ( w / w), 85% or more of the consecutive batches of the alkylated cyclodextrin composition have a chlorine level of less than 0.08% (w / w), 90% or more of the consecutive batches of the alkylated cyclodextrin composition have a chlorine level of less than 0.08% (w / p), 95% or more of the consecutive batches of the alkylated cyclodextrin composition have a chlorine level of less than 0.08% (w / w), 98% or more of the consecutive batches of the alkylated cyclodextrin composition have a chlorine level of less than 0.08% (w / w) , 50% or more of the lots c Consecutives of the alkylated cyclodextrin composition have a dechloride level of less than 0.05% (w / w), 65% or more of the consecutive lots of the alkylated cyclodextrin composition have a dechloride level of less than 0.05% (w / w), 75 % or more of the consecutive batches of the alkylated cyclodextrin composition have a chloride level of less than 0.05% (w / w), 80% or more of the consecutive batches of the alkylated cyclodextrin composition have a chloride level of less than 0.05% (w / w) ), 85% or more of the consecutive batches of the alkylated cyclodextrin composition have a chloride level of less than 0.05% (w / w), 90% or more of the consecutive batches of the alkylated cyclodextrin composition have a chloride level of less than 0, 05% (w / w), 95% or more of the consecutive batches of the alkylated cyclodextrin composition have a chloride level of less than 0.05% (w / w), or 98% or more of the consecutive batches of the alkylated cyclodextrin composition Alkylated cyclodextrin has a chloride level of less than 0.05% (w / w).

Preparation of Alkylated Cyclodextrin Compositions

[00115] The present invention describes several methods for the preparation of an alkylated cyclodextrin composition. In general, a non-derivatized cyclodextrin starting material in a neutral to alkaline aqueous medium is exposed to a substituent precursor. The substituent precursor can be added incrementally, or as a cake, and the substituent precursor can be added before, during, or after exposure of the cyclodextrin starting material to the optionally aqueous alkaline medium. Additional alkaline material or buffering material can be added as needed to maintain the pH within a desired range. The derivatization reaction can be conducted from room temperature to elevated temperatures. Once the derivatization has proceeded to the desired extent, the reaction is optionally quenched by the addition of an acid. The reaction medium is further processed (for example, solvent precipitation, filtration, centrifugation, evaporation, concentration, drying, chromatography, dialysis, and / or ultrafiltration), to remove unwanted materials and form the target composition. After final processing, the composition can be in the form of a solid, liquid, semi-solid, gel, syrup, paste, powder, aggregate, granule, pellet, compressed material, reconstitutable solid, suspension, glass, crystalline mass, amorphous mass, particulate, bead, bead, or wet dough.

[00116] The invention provides a process for producing an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, optionally having a predetermined degree of substitution, the process comprising: combining an unsubstituted cyclodextrin starting material with an alkylating agent in an amount sufficient to affect the predetermined degree of substitution in the presence of an alkali metal hydroxide; conducting alkylation of cyclodextrin within a pH of 9 to 11 until residual unreacted cyclodextrin is less than 0.5% by weight, or less than 0.1%; add additional hydroxide in an amount sufficient to achieve the degree of substitution, and allow the alkylation to proceed to completion; and add additional hydroxide to destroy any residual alkylating agent.

[00117] The addition of an additional hydroxide can be conducted using an amount of hydroxide, and under conditions (i.e., amount of additional hydroxide added, temperature, length of time during which the hydrolysis of the alkylating agent is conducted), such as that the level of residual alkylating agent in the aqueous crude product is reduced to less than 20 ppm, or less than 2 ppm.

[00118] It is possible that the reaction medium, or the partially purified aqueous solution, will comprise unreacted alkylating agent. The alkylating agent can be degraded in situ by adding an additional alkalizing agent, or by heating a solution containing the agent. The degradation of an excess alkylating agent will be required, where unacceptable amounts of alkylating agent are present in the reaction medium following termination of the mixture. The alkylating agent can be degraded in situ by adding an additional alkalizing agent, or by heating a solution containing the agent.

[00119] Degradation can be driven by: exposure of the reaction medium to an elevated temperature of at least 60 ° C, at least 65 ° C, or 60 ° C to 85 ° C, 60 ° C to 80 ° C, or 60 ° C to 95 ° C for a period of at least 6 hours, at least 8 hours, 8 hours to 12 hours, 6 hours to 72 hours, or 48 hours to 72 hours, thereby degrading the alkylating agent in situ, and reducing the amount of, or eliminating the alkylating agent in the aqueous liquid.

[00120] After the reaction has been conducted as described here, the aqueous medium containing the alkylated cyclodextrin can be neutralized at a pH of 7, in order to quench the reaction. The solution can then be diluted with water in order to lower the viscosity, particularly if further purification is to be conducted. Additional purifications may be employed, including, but not limited to, diafiltration in an ultrafiltration unit to purge the solution from reaction by-products, such as salts (eg, NaCl if sodium hydroxide was used as the base), and other by-products low molecular weight. The product can additionally be heated by ultrafiltration. The product solution can then be treated with activated carbon in order to improve its color, reduce biocharge, and substantially remove one or more impurities from drug degradation. The product can be isolated by a suitable drying technique, such as lyophilization, spray drying, or vacuum drum drying.

[00121] The reaction can initially be prepared by dissolving an unsubstituted a-, β-, or Y-cyclodextrin starting material in an aqueous base solution, usually a hydroxide, such as lithium, sodium, or potassium hydroxide . The base is present in a catalytic amount (i.e., a molar ratio of less than 1: 1 relative to cyclodextrin), to achieve a predetermined or desired degree of substitution. That is, the base is present in an amount less than a molar equivalent for each hydroxyl sought to be derivatized into the cyclodextrin molecule. Because the cyclodextrins become increasingly soluble in aqueous solution as the temperature is raised, the aqueous reaction mixture containing base and cyclodextrin must be raised to a temperature of 50 ° C, to ensure complete dissolution. Stirring is generally employed throughout the entire alkylation reaction.

[00122] After the dissolution is completed, the alkylating agent is added to initiate the alkylation reaction. The total amount of alkylating agent added through the entire reaction will generally be in excess of the stoichiometric amount required to complete the reaction relative to the amount of cyclodextrin, since some of the alkylating agent is hydrolyzed and / or otherwise destroyed / degraded during the reaction, such that it is not available for use in the alkylation reaction. The exact amount of alkylating agent to use at a desired degree of substitution can be determined through the use of test courses. The total amount of alkylating agent required to complete the reaction can be added prior to the initiation of the reaction. Because the system is aqueous, the reaction is usually conducted at a temperature between 50 ° C and 100 ° C. The reaction can be conducted at a temperature less than 100 ° C, so that specialized pressure equipment is not required. In general, a temperature of 65 ° C to 95 ° C is adequate.

[00123] During the initial reaction phase (here referred to as the pH control phase), care must be taken to monitor the pH, and keep it at least basic, or at a pH of 8 to 11. Monitoring the pH can be carried out conventionally as by using a standard pH meter. The pH adjustment can be carried out by adding an aqueous hydroxide solution, for example, a 10-15% solution. During the initial pH control phase, the unreacted cyclodextrin is reacted to less than 0.5% by weight, or less than 0.1% by weight, of unreacted cyclodextrin remains in the solution. Substantially the total initial charge of cyclodextrin is thus reacted by being partially replaced, but to less than the predetermined desired degree of substitution. Residual cyclodextrin can be monitored through this entire initial phase, for example, by high performance liquid chromatography (HPLC) as described below, until a desired parameter of less than 0.5%, or less than 0.1 %, residual cyclodextrin starting material, has been achieved. The pH can be maintained and / or increased by adding hydroxide once heated to the reaction medium continuously, or in different amounts as small increments. The addition in small increments is particularly suitable.

[00124] Once an alkylation procedure has been standardized or optimized so that it is known that particular amounts of reagents can be combined in a procedure that produces the desired degree of substitution in conjunction with residual cyclodextrin lowers, then the procedure can simply be checked at the end, as opposed to through all or during the initial pH control, to ensure that a low level of residual (unreacted) cyclodextrin starting material has been achieved. The following table shows a relationship between the amount of butane sultone loaded in a reactor, and the average degree of substitution resulting from SAE-CD.

[00125] It is noted that the initial pH of the reaction medium can be above 11, for example, after combining the initial charge of cyclodextrin starting material and base, but before adding alkylating agent. After an alkylating agent has been added and the reaction begins, however, the pH drops rapidly, requiring the action of a base to maintain a basic pH of about 8 to about 11.

[00126] Once the residual unreacted cyclodextrin level has reached a desired level, for example, below 0.5% by weight, during the pH control stage, the pH can be raised above 11, for example , a level above 12, by adding additional base to trigger the reaction for completion. The pH can be at least 12, so that the reaction proceeds to a reasonable state, but not so high that the unreacted alkylating agent is hydrolyzed quickly rather than reacting with cyclodextrin. During this last phase of the reaction, additional replacement of the cyclodextrin molecule is carried out until the predetermined degree of substitution has been reached. The total amount of hydroxide added through the entire reaction is typically in the order of the stoichiometrically required amount, plus 10-20 mol% of excess relative to the amount of alkylating agent employed. The addition of more than 10-20% of excess is also feasible. The end point of the reaction, as noted above, can be detected by HPLC. A suitable temperature is 65 ° C to 95 ° C. The HPLC system typically employs an anion exchange analytical column with pulsed amperometric detection (PAD). The elution can be by gradient using a two solvent system, for example, Solvent A being 25 mM (millimolar) aqueous sodium hydroxide, and Solvent B being 1 M sodium nitrate in 250 mM sodium hydroxide.

[00127] Once the alkylation reaction is complete and the low residual cyclodextrin endpoint has been reached, additional hydroxide can be added to destroy and / or degrade any residual alkylation agent. Additional hydroxide is typically added in an amount of 0.5 to 3 molar equivalents relative to cyclodextrin, and the reaction medium is allowed to continue heating to 65 ° C to 95 ° C, typically for 6 hours to 72 hours.

[00128] After the destruction of the residual alkylating agent, the resulting crude product can be further treated to produce a final product by being diluted, diafiltered to reduce or rid the product of low molecular weight components, such as salts, concentrated carbon, treated, and dried.

[00129] The pH is initially monitored to ensure that it remains at 8 to 11 as the alkyl derivatization reaction proceeds. At this early stage, the addition of a hydroxide to facilitate alkylation can be in stages, or in stages. Monitoring the pH of the reaction ensures that the reaction can be controlled, such that the total initial stock of cyclodextrin starting material is essentially reacted to the extent of effecting, on average, at least one substitution of alkyl per cyclodextrin molecule. The total cyclodextrin reagent is thus consumed at the beginning of the process, so that the level of residual (unreacted) cyclodextrin in the crude product is low, relative to the crude product produced by a process that initially characterizes a combination of stoichiometric quantity or in excess of base with cyclodextrin and alkylating agent, and allowing the reaction to proceed uncontrolled. After the total charge of cyclodextrin starting material has been partially reacted, the remaining hydroxide can be added to trigger the reaction for completion by finishing the alkyl substitution to the desired predetermined degree. After the initial charge of cyclodextrin has been consumed in the first pH controlled phase, the rate of hydroxide addition is not critical. In this way, the hydroxide can be added (for example, as a solution) continuously, or in different stages. In addition, the pH of the reaction medium should be kept above about 12, so that the reaction rate is commercially useful.

Impurity Reduction and Removal in a Cyclodextrin Composition

[00130] The control of the initial pH provides a means for reducing certain by-products from the reaction mixture. For example, an acid is produced as a result of alkylation, and the pH of the reaction mixture tends to decrease (that is, become more acidic) as the reaction proceeds. On the one hand, the reaction is kept basic because if the reaction medium becomes acidic, then the reaction will slow down considerably, or cease. Consequently, the pH of the reaction medium must be maintained at a level of at least 8 by the addition of aqueous hydroxide as needed. On the other hand, if the pH is allowed to exceed a certain level, for example, a pH greater than 12, then the reaction can produce a high level of by-products, such as 4-hydroxyalkylsulfonate and bis-sulfoalkyl ether, thereby consuming the alkylating agent starting material. By monitoring the pH of the reaction solution, and maintaining the pH at 8 to 12, or 8 to 11, the reaction proceeds, while producing a relatively low level of by-products, and a relatively clean reaction mixture containing relatively low levels of the by-products. mentioned above, is provided.

[00131] The above reference to a reagent being provided in an amount that is "stoichiometrically sufficient", and the like, is with respect to the amount of reagent needed to completely derivatize the cyclodextrin of interest to a desired degree of substitution.

[00132] As used herein, an "alkali metal hydroxide" refers to LiOH, NaOH, KOH, and the like. If it is desired to produce a product suitable for parenteral administration, then NaOH can be used.

[00133] The degree of substitution can be controlled by the use of correspondingly lower or higher amounts of alkylating agent, depending on whether a lower or higher degree of substitution is desired. Generally, the degree of substitution that can be achieved is an average of from 4.5 to 7.5, 5.5 to 7.5, or 6 to 7.1.

[00134] The crude product of the process here, that is, the product obtained after the destruction of the residual alkylating agent, contains a lower level of residual cyclodextrin than that produced by a process in which the base is initially added in a single charge, and is provided as an additional feature of the invention. The crude product produced by the process of this invention typically contains less than 0.5% by weight of residual cyclodextrin, or less than 0.1%. As explained below, the crude product is also advantageous in that it contains very low levels of residual alkylating agent.

[00135] Typically, the crude aqueous cyclodextrin product solution obtained after the destruction of the residual alkylating agent is purified by ultrafiltration, a process in which the crude product is contacted with a semipermeable membrane that passes low molecular weight impurities through of the membrane. The molecular weight of impurities passed through the membrane depends on the cut in molecular weight of the membrane. For the present invention, a membrane having a molecular weight cut of 1,000 Daltons ("Da") is typically employed. Diafiltrations and / or ultrafiltrations can be conducted with filtration membranes having a molecular weight cut of 500 Da to 2,000 Da, 500 Da to 1,500 Da, 750 Da to 1,250 Da, or 900 Da to 1,100 Da, or about 1,000 Da. The desired product that is in the retainer is then further treated with activated carbon to substantially remove impurities from drug degradation. The crude aqueous cyclodextrin product solution (that is, obtained after destruction of the residual alkylating agent, but before purification) is advantageous in that it contains less than 2 ppm residual alkylating agent based on the weight of the solution, less than than 1 ppm, or less than 250 ppb. The crude solution can also contain essentially no residual alkylating agent.

[00136] A final commercial product can be isolated at this point by, for example, filtration, to remove activated carbon, followed by evaporation of water (via, for example, distillation, spray drying, lyophilization, and the like). The final product produced by the present invention advantageously contains very low residual levels of alkylating agent, for example, less than 2 ppm, based on the weight of the dry final product (i.e., containing less than 10% by weight water), less than 1 ppm, less than 250 ppb, or essentially no residual alkylating agent. The final product containing less than 250 ppb of alkylating agent is, therefore, provided as an additional feature of the invention. The alkylating agent is reduced after completion of the alkylation to the desired degree of substitution by alkaline hydrolysis treatment as previously described, that is, by adding extra hydroxide solution in an amount, and under conditions sufficient to reduce the amount of agent. of unreacted alkylation in the dry product at the desired level below 2 ppm, less than 1 ppm, or less than 250 ppb.

[00137] The activated carbon suitable for use in the process of the present invention can be free of phosphate, and can be powder or granular, or a suspension or slurry produced therefrom. Generally, phosphate-free activated carbon is carbon that has not been activated using, or otherwise exposed to, phosphoric acid.

[00138] The raw material sources for activated carbon can be carbonaceous materials, such as nutshells, peat, wood, coconut, lignite, coal, and petroleum tar. Raw materials can be exposed to activation or physical, or chemical.

[00139] The physical activation of the raw material proceeds through the use of gases, and occurs through carbonization, activation / oxidation, or combinations of these. In carbonization, the raw material is pyrolysed at temperatures in the range of 600-900 ° C in the absence of oxygen (for example, in an inert atmosphere with argon or nitrogen). Upon activation / oxidation, the raw material is exposed to oxidation atmospheres (for example, carbon dioxide, oxygen, or steam) at temperatures above 250 ° C (for example, in the temperature range of 600-1200 ° C).

[00140] Chemical activation occurs before carbonization in which the raw material is impregnated with a chemical. In some embodiments, the chemical is an acid, a strong base, or a salt. In some embodiments, the activating chemical is phosphoric acid, potassium hydroxide, sodium hydroxide, calcium chloride, or zinc chloride. In some embodiments, after chemical activation, the raw material is carbonized at a lower temperature than used with a raw material that did not support chemical activation. In some embodiments, after chemical activation, the raw material is carbonized at 450-900 ° C.

[00141] A wide variety of activated carbon is available. For example, Norit-Americas markets more than 150 degrees and different varieties of activated carbon under trademarks, such as, DARCO®, HYDRODARCO®, NORIT®, BENTONORIT®, PETRODARCO®, and SORBONORITR. Carbons differ in particle size, application, activation method, and utility. For example, some activated carbons are optimized for removing color and / or aroma. Other activated carbons are optimized for removing protein, mineral, and / or amino acid fractions, or for whitening solutions.

[00142] Activated carbons suitable for use in accordance with the present invention include, but are not limited to: DARCOR 4X12, 12X20, or 20x40 granular lignite, steam activated (Norit Americas, Inc., Amersfoort, NE); DARCOR S 51 HF (from lignite, activated steam, powder); and SHIRASAGI® DC-32 powder or granular wood carbon, activated zindo chloride (Takeda Chemical Industries, Ltd., Osaka, JP).

[00143] Carbon that is activated with phosphoric acid, as used in the prior art for the purification of alkyl ether cyclodextrins, is generally suitable for use with the present invention, and includes: DARCO® KB-G, DARCO® KB-B and DARCO ® KB-WJ, as well as NORIT® CASP and NORIT® CN1.

[00144] The present invention provides a process for preparing an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, the process comprising: (a) mixing a cyclodextrin with an alkylating agent to form a reaction medium comprising an alkylated cyclodextrin, one or more unwanted components, and one or more drug-degrading impurities; (b) conducting one or more separations to remove the one or more unwanted components from the reaction medium to form a partially purified solution comprising the alkylated cyclodextrin and one or more drug degradation impurities, in which one or more separations they are ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, or dialysis; and (c) treating the partially purified solution with a phosphate-free activated carbon, and production of alkylated cyclodextrin, in which the phosphate-free activated carbon was not activated using zinc chloride or steam.

[00145] The present invention also provides a process for the preparation of an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, the process comprising: (a) mixing a cyclodextrin with an alkylating agent to form a reaction medium comprising an alkylated cyclodextrin, one or more unwanted components, and one or more drug-degrading impurities; (b) conducting one or more separations to remove the one or more unwanted components from the reaction medium to form a partially purified solution comprising the alkylated cyclodextrin and one or more drug degradation impurities, in which one or more separations they are ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, or dialysis; and (c) treating the partially purified solution with a phosphate-free activated carbon having a residual conductivity of 10 μS or less, and production of alkylated cyclodextrin, in which the phosphate-free activated carbon was not activated using zinc chloride or steam.

[00146] In some embodiments, the phosphate level in the alkylated cyclodextrin composition is less than 200 ppm, less than 150 ppm, less than 125 ppm, less than 100 ppm, less than 95 ppm, less than 90 ppm, less than 85 ppm, less than 80 ppm, less than 75ppm, less than 70 ppm, less than 65 ppm, less than 60 ppm, less than 55 ppm, less than 50 ppm, less than 45 ppm, less than 40 ppm, less than 35 ppm, less than 30 ppm, less than 20 ppm, less than 15 ppm, less than 10 ppm, less than 10 ppm, less than 10 ppm, less than 10 ppm. In some embodiments, the phosphate level in the alkylated cyclodextrin composition is 200 ppm at 5 ppm, 150 ppm at 5 ppm, 125 ppm at 5 ppm, 100 ppm at 5 ppm, 75 ppm at 5 ppm, 50 ppm at 5 ppm, 150 ppm to 10 ppm, 125 ppm to 10 ppm, 100 ppm to 10 ppm, or 75 ppm to 10 ppm.

[00147] The loading rate of activated carbon ultimately depends on the amount or concentration of the alkylated cyclodextrin, color forming agents, and drug-degrading agents in solution, as well as the physical properties of the activated carbon used. In general, the weight ratio of a cyclodextrin to activated carbon is 5: 1 to 10: 1, 6: 1 to 9: 1, 7: 1 to 9: 1, 8: 1 to 9: 1, 8.3: 1 to 8.5: 1, 8.4: 1 to 8.5: 1, or 8.44: 1 by weight per treatment cycle.

[00148] As used herein, "treatment cycle" refers to a contact of a predetermined amount of a cyclodextrin composition with a predetermined amount of activated carbon. A treatment cycle can be carried out as a single treatment, or as a multiple-pass treatment (recycling).

[00149] The Examples provided here detail the procedures used to evaluate and compare the efficiency of different grades, batches, sources, and types of activated carbon in removing one or more components of drug degradation and one or more components of color formation present in an SAE-CD internal process medium or solution. In general, an internal process medium or solution is treated with activated carbon, and stirred for 120 min. If a loose particulate or activated carbon powder form is used, it can be removed by filtering a liquid containing the carbon through a filtration medium to provide the decanted solution.

[00150] The filtration membrane can include nylon, TEFLONR, PVDF, or other compatible material. The pore size of the filtration membrane can be varied as needed according to the particle size or molecular weight of species being separated from the SAE-CD in a solution containing it.

[00151] The Examples provided herein detail the procedures for conducting one or more separations and / or purifications in an aqueous reaction medium of the present invention. A reaction solution is diluted with aqueous solution, and subjected to diafiltration during which the volume of the retainer is kept substantially constant. Diafiltration can be conducted over a 1,000 Da filter, such that one or more unwanted components pass through the filter, but most of the alkyl ether present in the alkylated cyclodextrin composition is retained in the retainer, preferably rather than passing through the filtrate. Ultrafiltration is then conducted, allowing the volume of the retainer, thereby decreasing the concentration of the retainer. A filter having a molecular weight cut of about 1,000 Da can also be used for ultrafiltration. The retainer comprises alkylated cyclodextrin, which can then be treated with activated carbon, as described herein.

[00152] The one or more unwanted components may include, but are not limited to, low molecular weight impurities (i.e., impurities having a molecular weight of about 500 Da or less), water-soluble ions and / or insoluble ions in water (i.e., salts), hydrolyzed alkylating agent, 5- (hydroxymethyl) -2-furaldehyde, unreacted cyclodextrin starting material, degraded cyclodextrin species (for example, degraded and / or open ring species formed from unreacted cyclodextrin, partially reacted cyclodextrin, and / or SAE-CD), unreacted alkylating agent (e.g., 1,4-butane sultone), and combinations thereof.

[00153] In some embodiments, the compositions of the present invention are substantially free of one or more drug-degrading agents. The presence of one or more drug-degrading agents can be determined, among others, by UV / visible spectrophotometry ("UV / vis"). As used herein, a "drug-degrading agent", or "drug-degrading impurity", refers to a species, fraction, and the like, that degrade certain active components in the aqueous solution. It will be understood that a drug-degrading agent may not degrade all drugs with which an alkylated cyclodextrin composition can be combined, depending on the chemical structure of the drug and its degradation trajectories. In some embodiments, a kind of drug degradation has an absorption in the UV / visible region of the spectrum, for example, maximum absorption at a wavelength from 245 nm to 270 nm.

[00154] The presence of drug-degrading agents in the alkylated cyclodextrin composition can be measured by UV / vis in absorbance units (A.U.). In some embodiments, the alkylated cyclodextrin composition has an absorption of less than 1 AU, less than 0.9 AU, less than 0.8 AU, less than 0.7 AU, less than 0.6 AU , 0.5 AU, less than 0.4 AU, less than 0.3 AU, less than 0.2 AU, or less than 0.1 AU

[00155] The absorbance of the solution becomes linear with the concentration according to the formula:

[00156] A = εlc

[00157] in which

[00158] A = absorbance

[00159] ε = extinction doefficient

[00160] l = path length

[00161] c = molar concentration.

[00162] The presence of a drug-degrading agent in the alkylated cyclodextrin composition can be measured using UV / vis spectrophotometry at a wavelength of 245 to 270 nm using a cell having a path length of 1 cm. In some embodiments, the alkylated cyclodextrin composition has an absorption of less than 1 A.U. at a wavelength of 245 nm to 270 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, less than 1 A.U. at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, less than 1 A.U. at a wavelength of 245 nm to 270 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, less than 1 A.U. at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.9 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.9 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.9 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.9 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.8 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.8 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.8 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.8 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.7 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.7 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.7 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.7 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.6 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.6 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.6 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.6 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.5 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.5 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.5 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.5 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.4 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.4 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.4 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.4 or less A.U. at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.3 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition, 0.3 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.3 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.3 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.2 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.2 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.2 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, or 0.2 A.U. or less at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution.

[00163] The presence of a color forming agent in the alkylated cyclodextrin composition can be measured using UV / vis spectrophotometry at a wavelength of 320 nm to 350 nm using a cell having a path length of 1 cm. In some embodiments, the alkylated cyclodextrin composition has an absorption of less than 1 A.U. at a wavelength of 320 nm to 350 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, less than 1 A.U. at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, less than 1 A.U. at a wavelength of 320 nm to 350 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, less than 1 A.U. at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.9 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.9 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.9 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.9 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.8 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.8 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.8 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.8 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.7 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.7 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.7 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.7 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.6 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.6 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.6 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.6 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.5 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.5 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.5 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.5 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.4 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.4 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.4 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.4 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.3 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition, 0.3 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.3 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, 0.3 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution, 0.2 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per ml of solution, 0.2 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution, 0.2 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per ml of solution, or 0.2 A.U. or less at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per ml of solution.

[00164] Not being bound by any particular theory, a drug-degrading agent, species, or fraction, may include one or more low molecular weight species (for example, a species having a molecular weight less than 1,000 Da), such as, but not limited to, a species generated as a side product and / or decomposition product in the reaction mixture. As such, drug degradation species include, but are not limited to, a glycosidic fraction, an open ring cyclodextrin species, a reducing sugar, a glucose degradation product (for example, 3,4-dideoxyglucosone- 3-ene, carbonyl-containing degradants such as 2-furaldehyde, 5-hydroxymethyl-2-furaldehyde and the like), and combinations thereof.

[00165] In some embodiments, the alkylated cyclodextrin composition comprises less than 1% by weight, less than 0.5% by weight, less than 0.2% by weight, less than 0.1% by weight , less than 0.08% by weight, or less than 0.05% by weight, of an alkali metal halide salt.

[00166] In some embodiments, the alkylated cyclodextrin composition comprises less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, less than 0.1% by weight , less than 0.08% by weight, or less than 0.05% by weight, of a hydrolyzed alkylating agent.

[00167] In some embodiments, the alkylated cyclodextrin composition comprises less than 500 ppm, less than 100 ppm, less than 50 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm, less than 2 ppm, less than 1 ppm, less than 500 ppb, or less than 250 ppb, of an alkylating agent.

[00168] In some embodiments, the alkylated cyclodextrin composition comprises less than 0.5% by weight, less than 0.2% by weight, less than 0.1% by weight, or less than 0.08 % by weight of non-derivatized cyclodextrin.

[00169] By "complexed" is significant "being part of a clathrate or inclusion complex with, that is, a therapeutic agent" complexed "is part of a clathrate or inclusion complex with an alkylated cyclodextrin. The term" major portion " refers to 50% or greater, by weight, or on a molar basis. Thus, a formulation according to the present invention can contain an active agent of which more than about 50% by weight is complexed with an alkylated cyclodextrin The actual percentage of active agent that is complexed will vary according to the complexation equilibrium bond constant that characterizes the complexation of a specific cyclodextrin with a specific active agent The invention also includes embodiments in which the active agent is not complexed with cyclodextrin, or where only a minor portion of the active agent is complexed with the alkylated cyclodextrin. It should be noted that an alkylated cyclodextrin can form one or more ionic bonds with a c positively charged compound. This ionic association can occur regardless of whether the positively charged compound is complexed with cyclodextrin by inclusion complexation.

[00170] As shown in FIG. 6, after ultrafiltration of the SBE-CD crude product, impurities, such as β-cyclodextrin and 4-hydroxybutane-l-sulfonic acid (4-HBSA), are present. After a second column with activated carbon, the amount of impurities of β-cyclodextrin and 4-hydroxybutane-1-sulfonic acid was reduced. However, as shown in FIG. 6, there are high amounts of chloride present in the product after the two columns.

[00171] In the purification process using activated carbon, although the drug-degrading agents have been reduced, high amounts of chloride are present in the alkylated cyclodextrin product. This high amount of chloride in the alkylated cyclodextrin product can react with an active agent, and cause degradation of the active agent. Therefore, it is necessary to reduce the levels of chloride in the alkylated cyclodextrin product, in particular when the active agent is sensitive to chloride.

[00172] The determination of whether an active agent is sensitive to chloride can be determined by a person skilled in the art using known techniques.

[00173] As shown in FIG. 7, after ultrafiltration, the residual chloride level drops to approximately zero. After further purification using two columns of activated carbon, the chloride is added back into the SBE-CD solution.

Análise de Cor de Solução de SBE6-6-β-CD

[00174] During the purification of activated carbon, water is operated through the activated carbon column until the conductivity is at a constant level before adding the SBE-CD solution. The following Table provides details of the amount of water and the resulting conductivity levels measured for activated carbon columns. As seen in the Table, even in batches where 70,000 liters of water were used to wash the activated carbon before adding the SBE-CD solution, a chloride impurity was found in the final SBE-CD solution.

Color Analysis of SBE6-6-β-CD Solution

[00175] A more extensive examination of the processing before and during circulation with the activated carbon shows that the greatest addition of chloride occurs in the first few minutes of circulation of the SBE-CD solution through the activated carbon bed. As shown in FIG. 8, the chloride impurity level for two commercial batches of SBE-CD is approximately zero after ultrafiltration, and increases substantially after treatment with activated carbon during the first 5 minutes, with the level dropping after 10 and 20 minutes.

[00176] As shown in FIG. 9, there is a direct correlation between the level of chloride transferred to the SBE-CD solution and the level of conductivity at the end of the water wash. In FIG. 9, the level of conductivity in a first column of activated carbon and a second column of activated carbon was measured. The conductivity levels were found to be correlated with the residual chloride level in the final SBE-CD solid, as measured by the ZIC pHILIC method for residual chloride content. Therefore, the conductivity measurement obtained at the end of the washing process correlates with the level of residual chloride in the final SBE-CD product.

[00177] The chloride level of the alkylated cyclodextrin composition can be determined using any method commonly used by a person skilled in the art. In some embodiments, the chloride level is measured using charged aerosol (CAD) detection.

[00178] In some embodiments, the chloride level, as measured by weight (w / w) ratio in the alkylated cyclodextrin composition, is 1% or less, 0.9% or less, 0.8% or less, 0 , 7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0, 09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02 % or less, or 0.01% or less. In some embodiments, the chloride level in the alkylated cyclodextrin composition is 1% to 0.01%, 0.9% to 0.01%, 0.8% to 0.01%, 0.7% to 0.01 %, 0.6% to 0.01%, 0.5% to 0.01%, 0.4% to 0.01%, 0.3% to 0.01%, 0.2% to 0.01 %, 0.1% to 0.01%, 0.09% to 0.01%, 0.08% to 0.01%, 0.07% to 0.01%, 0.06% to 0.01 %, 0.05% to 0.01%, 0.04% to 0.01%, or 0.03% to 0.01%.

[00179] As used herein, the term "conductivity" refers to the ability of an aqueous solution to conduct an electrical current between two electrodes at a particular temperature. A current flows through ion transport in solution. Therefore, with an increased amount of ions present in the aqueous solution, the solution will have a higher conductivity. In some embodiments, the temperature at which conductivity measurements are made can be 4 ° C to 37 ° C. In some embodiments, the temperature at which conductivity measurements are made can be 15 ° C to 25 ° C. In some embodiments, the temperature at which conductivity measurements are made is 25 ° C.

[00180] The unit of measurement for conductivity is microSiemens per centimeter (μS / cm).

[00181] The conductivity of the activated carbon water washing eluent can be determined using any method commonly used by a person skilled in the art. In some embodiments, conductivity is measured using a conductivity meter. In some embodiments, the conductivity is mixed using ion chromatography.

[00182] In some embodiments, the conductivity of the phosphate-free activated carbon water washing eluant is measured before the addition of the partially purified alkylated cyclodextrin solution. In some embodiments, the conductivity of the water wash eluent from the activated carbon prior to the addition of the partially purified alkylated cyclodextrin solution is less than 35 μS, less than 34 μS, less than 33 μS, less than 32 μS, less than 31 μS, less than 30 μS, less than 29 μS, less than 28 μS, less than 27 μS, less than 26 μS, less than 25 μS, less than 24 μS, less than than 23 μS, less than 22 μS, less than 21 μS, less than 20 μS, less than 19 μS, less than 18 μS, less than 17 μS, less than 16 μS, less than 15 μS, less than 14 μS, less than 13 μS, less than 12 μS, less than 11 μS, less than 10 μS, less than 9 μS, less than 8 μS, less than 7 μS, less than 6 μS, less than 5 μS, less than 4 μS, less than 3 μS, less than 2 μS, or less than 1 μS. In some embodiments, the conductivity of the water wash eluent from the activated carbon prior to the addition of the partially purified alkylated cyclodextrin solution is 10 μS to 15 μS, 5 μS to 15 μS, 5 μS to 10 μS, 4 μS to 10 μS, 3 μS to 10 μS, or 4 μS to 8 μS.

[00183] In some embodiments, the activated carbon is washed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times before adding the cyclodextrin solution partially purified alkylate. In some embodiments, the activated carbon is washed 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more, times before adding the partially purified alkylated cyclodextrin solution.

[00184] Even when the activated carbon in the column is washed with water, there may be inadequate wetting of the activated carbon. In the washing procedure, there is no way to control the channeling through the carbon bed. It is believed that by further washing the carbon completely before circulating the alkylated cyclodextrin solution, it will reduce or remove any residual chloride addition from the alkylated cyclodextrin product composition.

[00185] In some embodiments, the activated carbon is added to a dedicated tank system with an agitator and a sieve system. The activated carbon is charged, followed by washing with several portions of water at a rate of agitation determined for a specified period of time. After washing with water, the water layer is removed from the dedicated tank, and additional water washing occurs. After additional water washes, the conductivity of the activated carbon is determined, and when the conductivity is below a predetermined level, the carbon is suspended in water and pumped into the carbon housings. The activated carbon would then be ready for addition of the alkylated cyclodextrin solution. The predetermined level of conductivity can be, for example, less than 35 μS, less than 34 μS, less than 33 μS, less than 32 μS, less than 31 μS, less than 30 μS, less than than 29μS, less than 28μS, less than 27 μS, less than 26 μS, less than 25 μS, less than 24 μS, less than 23 μS, less than 22μS, less than 21 μS, less than 20μS, less than 19 μS, less than 18 μS, less than 17 μS, less than 16 μS, less than 15 μS, less than 14 μS, less than 13 μS, less than 12 μS, less than 11 μS, less than 10 μS, less than 9 μS, less than 8 μS, less than 7 μS, less than 6 μS, less than 5 μS, less than 4 μS, less than 3 μS, less than 2 μS, or less than 1 μS.

[00186] Agitation can be measured in revolutions per minute (rpm). In some embodiments, the rate of agitation can vary, for example, from 5 rpm to 300 rpm. For example, the agitation rate can be 5 rpm, 10 rpm, 20 rpm, 30 rpm, 40 rpm, 50 rpm, 60 rpm, 70 rpm, 80 rpm, 90 rpm, or 100 rpm. The stirring time can vary from 1 minute to 5 days. The stirring time can be, for example, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 2 days, 3 days, or 4 days. In some embodiments, the stirring time is 5 minutes to 1 hour, 5 minutes to 2 hours, 5 minutes to 3 hours, 5 minutes to 4 hours, 5 minutes to 5 hours, 10 minutes to 1 hour, 10 minutes to 2 hours , 10 minutes to 3 hours, 10 minutes to 4 hours, 20 minutes to 1 hour, 20 minutes to 2 hours, 20 minutes to 3 hours, 20 minutes to 4 hours, 30 minutes to 1 hour, 30 minutes to 2 hours, 30 minutes to 3 hours, or 30 minutes to 4 hours.

[00187] In some embodiments, the tank system is kept at room temperature (25 ° C) during the water wash process. In some embodiments, the tank system can be heated during the water wash process. In some embodiments, the temperature can vary, for example, from 30 ° C to 100 ° C. For example, the cooling temperature can be 30 ° C, 40 ° C, 50 ° C, 60 ° C, 70 ° C, 80 ° C, 90 ° C, or 100 ° C. The warm-up time can vary from 1 minute to 5 days. The warm-up time can be, for example, 5 minutes to 4 days, 5 minutes to 60 minutes, 10 minutes to 50 minutes, 20 minutes to 40 minutes, 30 minutes to 60 minutes, 2 hours to 24 hours, 3 hours to 12 hours, 4 hours to 10 hours, 5 hours to 9 hours, 6 hours to 8 hours, 2 days to 4 days, or 3 days to 4 days. In some embodiments, the warm-up time is 5 minutes to 1 hour, 5 minutes to 2 hours, 5 minutes to 3 hours, 5 minutes to 4 hours, 5 minutes 5 hours, 10 minutes 1 hour, 10 minutes to 2 hours, 10 minutes 3 hours, 10 minutes 4 hours, 20 minutes 1 hour, 20 minutes 2 hours, 20 minutes 3 hours, 20 minutes to 4 hours, 30 minutes 1 hour, 30 minutes to 2 hours, 30 minutes to 3 hours, or 30 minutes to 4 hours.

[00188] In some embodiments, the activated carbon is washed in the carbon housing until a certain level of conductivity has been reached. The activated carbon would then be ready for addition of the alkylated cyclodextrin solution.

[00189] In some embodiments, the activated carbon is washed at a constant conductivity level, followed by the addition of a known amount of alkylated cyclodextrin solution through the activated carbon that is discharged before the addition of an additional alkylated cyclodextrin solution.

[00190] In some embodiments, the phrase "constant conductivity" means the conductivity of water after the contact of the activated carbon is approximately equal at two different time points. In this way, the activated carbon can be washed at "constant conductivity" if the conductivity of the water after contact of the activated carbon has not changed by more than an adjusted percentage over an adjusted amount of time. The adjusted percentage can be in the range of 1-25%, for example 10%, and the adjusted amount of time can be in the range of 10 minutes to 2 hours, for example 1 hour. Those skilled in the art understand that the adjusted percentage and the adjusted amount of time can be varied from these disclosed values, as appropriate. In other embodiments, the phrase "constant conductivity" can mean the conductivity of water before the contact of the activated carbon is approximately equal to the conductivity of the water after contact of the activated carbon.

[00191] In some embodiments, the activated carbon is subjected to a first carbon washing process comprising adding water, immersing the activated carbon in water, and draining the water. The water can be filled in a co-current direction, for example, from the top to the bottom, or a counter-current direction, for example, from the bottom to the top. In one embodiment, the activated carbon is allowed to immerse for an adjusted amount of time before the water is drained. For example, activated carbon can immerse for at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, 390 minutes, 420 minutes, 450 minutes, 480 minutes, or more. In one embodiment, the activated carbon is allowed to immerse for about 30 minutes. The first carbon washing process can be repeated any number of times. For example, the first carbon washing process can be repeated 1, 2, 3, 4, 5, or more times. In one embodiment, the first carbon washing process is repeated 3-4 times.

[00192] In some embodiments, the activated carbon may be subjected to a second carbon washing process after the first carbon washing process. The second carbon washing process may comprise draining water over the activated carbon. In some embodiments, the water is drained over the activated carbon in the same direction as the water was filled in the first carbon washing process. In other embodiments, the water is drained over the activated carbon in a different direction than the water was filled in the first carbon washing process. For example, water can be filled in the first carbon washing process in a countercurrent direction, and water can be drained over the activated carbon in the second carbon washing process in a co-current direction. The water can be drained over the activated carbon for an adjusted amount of time. For example, water can be drained over activated carbon for at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes , 150 minutes, 180 minutes, 210 minutes, 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, 390 minutes, 420 minutes, 450 minutes, 480 minutes, or more. For example, water can be drained over activated carbon for about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours. Water can be drained over activated carbon at a flow rate of at least 50 liters per hour, 100 liters per hour, 150 liters per hour, 200 liters per hour, 250 liters per hour, 300 liters per hour, 350 liters per hour , 400 liters per hour, 450 liters per hour, 500 liters per hour, or more. For example, water can be drained over activated carbon for about 100 liters per hour, about 200 liters per hour, about 300 liters per hour, about 400 liters per hour, about 500 liters per hour, about 600 liters per hour, about 700 liters per hour, about 800 liters per hour, about 900 liters per hour, or about 1,000 liters per hour. The second carbon washing process can be repeated any number of times. For example, the second carbon washing process can be repeated 1, 2, 3, 4, 5, or more times. In one embodiment, the second carbon washing process is repeated 3-4 times.

[00193] In some embodiments, the residual conductivity of the water is tested after the second carbon washing process. In one embodiment, if the residual conductivity is less than or equal to the desired amount, the carbon washing process is considered complete, but if the residual conductivity is greater than the desired amount, at least one of the first carbon and the second carbon washing process are repeated one or more times. The desired amount of residual conductivity can be 10 μS or less, 9 μS or less, 8 μS or less, 7 μS or less, 6 μS or less, or 5 μS or less.

[00194] The final yield of the alkylated cyclodextrin (in isolated and / or purified or partially purified form) obtained at the completion of the process will vary. The yield of alkylated cyclodextrin based on the cyclodextrin starting material can vary from 10% to 95%, 15% to 90%, 20% to 85%, 30% to 85%, 35% to 85%, 40% to 85% , 45% to 80%, 50% to 80%, 55% to 80%, 60% to 80%, 50% to 90%, 55% to 90%, 60% to 90%, 70% to 90%, 80 % to 90%, 60% to 98%, 70% to 98%, 80% to 98%, or 90% to 98%. In some embodiments, the final alkylated cyclodextrin yield based on the cyclodextrin starting material is 80% or greater, 85% or greater, 90% or greater, or 95% or greater.

Uses of the alkylated cyclodextrin compositions

[00195] Among other uses, an alkylated cyclodextrin composition of the present invention can be used to solubilize and / or stabilize a variety of different materials, and to prepare formulations for particular applications. The present alkylated cyclodextrin composition can provide enhanced solubility and / or enhanced chemical, thermochemical, hydrolytic and / or photochemical stability of other ingredients in a composition. For example, an alkylated cyclodextrin composition can be used to stabilize an active agent in an aqueous medium. An alkylated cyclodextrin composition can also be used to increase the solubility of an active agent in an aqueous medium.

The alkylated cyclodextrin composition of the present invention can include one or more active agents. The one or more active agents included in the composition of the present invention can have a wide range of water solubility, bioavailability and hydrophilicity. The active agents to which the present invention is particularly suitable include therapeutic agents insoluble in water, poorly soluble in water, slightly soluble in water, sparingly soluble in water, soluble in water, very soluble in water, hydrophobic, and / or hydrophilic. It will be understood by one skilled in the art that one or more active agents present in a composition of the present invention are independently selected on each occurrence of any known active agent and that disclosed herein. It is not necessary that the one or more active agents form a complex with the alkylated cyclodextrin, or form an ionic association with the alkylated cyclodextrin.

[00197] Compositions comprising an alkylated cyclodextrin and one or more active agents can be prepared by combining an alkylated cyclodextrin which is prepared by any of the processes described herein with the one or more active agents. In some embodiments, the combination comprises dissolving the alkylated cyclodextrin and one or more active agents in the same solvent. In some embodiments, the solvent is water. Some embodiments further include drying the solution comprising the alkylated cyclodextrin and the one or more active agents. The solution can be dried using any suitable medium including, but not limited to, freeze drying (lyophilization), spray drying, and fluid bed spray drying. Other embodiments include dry mixing of the alkylated cyclodextrin with the one or more active agents.

[00198] Active agents generally include physiologically or pharmacologically active substances that produce a systemic or localized effect or effects in animals and humans. Active agents also include pesticides, herbicides, insecticides, antioxidants, plant growth instigators, sterilizing agents, catalysts, chemical reagents, food products, nutrients, cosmetics, vitamins, sterility inhibitors, fertility instigators, microorganisms, flavoring agents , sweeteners, cleaning agents, pharmaceutically effective active agents, and other such compounds for pharmaceutical, veterinary, horticultural, domestic, food, culinary, agricultural, cosmetic, industrial, cleaning, confectionery, and flavoring applications. The active agent can be present in its neutral, ionic, salt, basic, acidic, natural, synthetic, diastereomeric, isomeric, enantiomerically pure, racemic, hydrate, chelate, derivative, analogous, or other common form.

[00199] Representative pharmaceutically effective active agents include nutrients and nutritional agents, hematological agents, endocrine and metabolic agents, cardiovascular agents, kidney and genitourinary agents, respiratory agents, central nervous system agents, gastrointestinal agents, anti-fungal agents, anti-agents -infectives, biological and immunological agents, dermatological agents, ophthalmic agents, antineoplastic agents, and diagnostic agents. Exemplary nutrient and nutritional agents include minerals, trace elements, amino acids, lipotropic agents, enzymes and chelating agents. Exemplary hematological agents include hematopoietic agents, antiplatelet agents, anticoagulants, coumarin and indandione derivatives, coagulants, thrombolytic agents, anti-sweating agents, hemorrhoid agents, antihemophilic agents, hemostatic agents, plasma and hemine expanders. Exemplary endocrine and metabolic agents include sex hormones, uterine active agents, bisphosphonates, antidiabetic agents, glucose-raising agents, corticosteroids, adrenocortical steroids, parathyroid hormone, thyroid drugs, growth hormones, posterior pituitary hormones, octreotide acetate, imiglucerase, calcitonin -salmon, sodium phenulbiturate, anhydrous betaine, cysteamine bitartrate, sodium benzoate and sodium phenylacetate, bromocriptine mesylate, cabergoline, gout agents, and antidotes.

[00200] Antifungal agents suitable for use with the alkylated cyclodextrin composition of the present invention include, but are not limited to, posaconazole, voriconazole, clotrimazole, ketoconazole, oxiconazole, sertaconazole, tetconazole, fluconazole, itraconazole and miconazol. Antipsychotic agents suitable for use with the alkylated cyclodextrin composition of the present invention include, but are not limited to, clozapine, prochlorperazine, haloperidol, thioridazine, thiotixene, risperidone, trifluoperazine hydrochloride, chlorpromazine, aripiprazole, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine, loxapine. fumarate, risperidone and ziprasidone.

Exemplary cardiovascular agents include nootropic agents, antiarrhythmic agents, calcium channel blocking agents, vasodilators, antiadrenergic / sympatholytic agents, renin angiotensin system antagonists, antihypertensive agent combinations, agents for pheochromocytoma, agents for hypertensive emergencies, agents antihyperlipidemic, antihyperlipidemic combination products, vasopressors used in shock potassium removal resins, disodium edetate, cardioplegic solutions, patent duct agents, and sclerosing agents. Exemplary renal and genitourinary agents include interstitial cystitis agents, sodium cellulose phosphate, anti-impotence agents, acetohydroxamic acid (aha), genitourinary irrigators, cysteine depleting agents, urinary alkalinizers, urinary acidifiers, anticholinergics, urinary cholinergics, phosphate binders. polymeric, vaginal preparations, and diuretics. Exemplary respiratory agents include bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, respiratory inhalants, nasal decongestants, respiratory enzymes, lung surfactants, antihistamines, non-narcotic antitussives, and expectorants. Exemplary central nervous system agents include CNS stimulants, narcotic agonist analgesics, narcotic agonist-antagonist analgesics, central analgesics, acetaminophen, salicylates, non-narcotic analgesics, non-steroidal anti-inflammatory agents, migraine agents, antiemetic / anti-vertigo agents, antianxiety agents, antidepressants, antipsychotic agents, cholinesterase inhibitors, non-barbiturate sedatives and hopnotics, non-prescription sleep aids, barbiturate and hypnotics sedatives, general anesthetics, injectable local anesthetics, anticonvulsants, muscle relaxants, antiparkinson agents, phosphate adenosine cholinergic muscle stimulants, disulfurize, smoke deterrents, riluzole, hyaluronic acid derivatives, and botulinum toxins. Exemplary gastrointestinal agents including H pylori agents, H2 histamine antagonists, proton pump inhibitors, sucralfate, prostaglandins, antacids, anticholinergics / gastrointestinal antispasmodics, mesalamine, sodium olsalazine, disodium balsalazide, sulfasalazine, malaboxy, tetraoxide, inflorescence, malaboxy, tetrahydrate, malaboxy, tetrahydrate, tetrahydroxide, tetrahydroxide, tetrahydroxide, tetrahydroxate, tetrahydroxide, tetrahydrate. , antiflatulent, lipase inhibitors, GI stimulants, digestive enzymes, gastric acidifiers, hydrocoleretics, gallstone solubilizing agents, mouth and throat products, systemic deodorizers, and anorectal preparations. Exemplary anti-infective agents including penicillins, cephalosporins and related antibiotics, carbapenem, monobactams, chloramphenicol, quinolones, fluoroquinolones, tetracyclines, macrolides, spectinomycin, streptogramins, vancomycin, oxalodinones, lincosamides, aminoglycosides, amino acids, amino acids , metronidazole, sulfonamides, nitrofurans, methenamines, folate antagonists, antifungal agents, antimalarial preparations, antituberculosis agents, amoebicides, antiviral agents, antiretroviral agents, leprostats, antiprotozoans, antihelmintics, and anti-infectious cdc agents. Exemplary biological and immunological agents including immune globulins, monoclonal antibody agents, antivenins, agents for active immunization, allergenic extracts, immunological agents, and antirheumatic agents. Exemplary dermatological agents include topical antihistamine preparations, topical anti-infective agents, anti-inflammatory agents, anti-psoriatic agents, anti-sebum products, arnica, astringents, cleansers, capsaicin, destructive agents, drying agents, enzyme preparations, topical immunomodulators, keratolytic agents , liver-derived complex, topical local anesthetics, minoxidil, eflornithine hydrochloride, photochemotherapy agents, pigment agents, topical ivy poison products, topical pyrimidine antagonist, zinc pyrithione, retinoids, rexinoids, scabies / pediculicides, curing agents wound, emollients, protectors, sunscreens and lotion bases, scouring pads and liniments, dressings and granules, and physiological irrigation solutions. Exemplary ophthalmic agents include glaucoma agents, stem cell stabilizers, ophthalmic antiseptics, ophthalmic phototherapy agents, eye lubricants, artificial tears, ophthalmic hyperosmolar preparations, and contact lens products. Exemplary antineoplastic agents include alkylating agents, antimetabolites, antimitotic agents, epipodophyllotoxins, antibiotics, hormones, enzymes, radiopharmaceuticals, platinum coordination complex, anthracenedione, substituted ureas, methylhydrazine derivatives, imidazotetrazine derivatives, DNA inhibitors, cytoproteinone agents biological response modifiers, retinoids, rexinoids, monoclonal antibodies, protein-tyrosine kinase inhibitors, sodium porfimer, mitotane (o, p'-ddd), and arsenic trioxide. Exemplary diagnostic agents include in vivo diagnostic aids, biological in vivo diagnostics, and radiopaque agents.

Exemplary active agents also include compounds that are sensitive to chloride levels. Exemplary chloride-sensitive active agents include proteasome inhibitors, such as bortezomib, disulfiram, epigalocatchin-3-gallate, salinosporamide A, and carfilzomib.

[00203] The active agents listed above should not be considered exhaustive, and are merely exemplary of the many embodiments considered within the scope of the invention. Many other active agents can be administered with the formulation of the present invention.

[00204] A formulation of the invention can be used to deliver two or more different active agents. Particular combinations of active agents can be provided in a formulation of the invention. Some combinations of active agents include: 1) a first drug from a first therapeutic class and a second different drug from the same therapeutic class; 2) a first drug from a first therapeutic class and a second drug from a different therapeutic class; 3) a first drug having a first type of biological activity and a second different drug having about the same biological activity; and 4) a first drug having a first type of biological activity and a second different drug having a second different type of biological activity. Exemplary combinations of active agents are described here.

[00205] An active agent contained within a formulation of the invention may be present as its pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds in which the active agent is modified by reacting it with an acid and / or base, as necessary, to form an ionically bonded pair. Examples of pharmaceutically acceptable salts include conventional non-toxic salts, or the quaternary ammonium salts of a compound formed, for example, of non-toxic inorganic and organic acids. Suitable non-toxic salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric, and others known to those skilled in the art. Salts prepared from organic acids, such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroximalic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, disulfonic, oxalic, isethionic ethane, and others known to those skilled in the art. Pharmaceutically acceptable salts suitable for use with the present invention can be prepared using an active agent that includes a basic or acidic group by conventional chemical methods. Suitable addition salts are found in Remington's Pharmaceutical Sciences (17th ed., Mack Publishing Co., Easton, PA, 1985), the relevant disclosure of which is thereby incorporated by reference in its entirety.

[00206] The present invention is also directed to a method for stabilizing an active agent, the method comprising providing an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, less than 500 ppm of a phosphate, and less than 0.5% of a chloride, in which the alkylated cyclodextrin composition has an absorption of less than 1 AU, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the composition of alkylated cyclodextrin per ml of solution in a cell having a path length of 1 cm; and combining the alkylated cyclodextrin composition with an active agent. In some embodiments, said absorption of less than 1 A.U. it is due to a drug-degrading agent.

[00207] The present invention is also directed to a method for stabilizing an active agent, the method comprising providing an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, less than 500 ppm of a phosphate, and less than 0.5% of a chloride, in which the alkylated cyclodextrin composition has an absorption of less than 1 AU, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the composition of alkylated cyclodextrin per ml of solution in a cell having a path length of 1 cm; and combining the alkylated cyclodextrin composition with an active agent. In some embodiments, said absorption of less than 1 A.U. it is due to a heat forming agent.

[00208] The method of stabilizing an active agent can be carried out, in which the composition comprising one or more active agents and an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, and less than 500 ppm of a phosphate, is present as a dry solution, a wet solution, an inhalable composition, a parenteral composition, a solid solution, a solid mixture, a granulate, a gel, and other active agent compositions known to those skilled in the art.

[00209] In some embodiments, the method of stabilizing an active agent provides 2% or less, 1.5% or less, 1% or less, or 0.5% or less, of a drug-degrading agent, or color forming agent, after the composition comprising one or more active agents, and an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, and less than 500 ppm of a phosphate, be maintained at a temperature of 80 ° C for a period of 120 minutes.

[00210] In some embodiments, the method of stabilizing an active agent provides 2% or less, 1.9% or less, 1.8% or less, 1.7% or less, 1.6% or less, 1.5 % or less, 1.4% or less, 1.3% or less, 1.2% or less, 1.1% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7 % or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less, of a chloride after the composition comprising one or more active agents and an alkylated cyclodextrin composition comprising an alkylated cyclodextrin and less than 500 ppm of a phosphate is maintained at a temperature of 80 ° C for a period of 120 minutes.

[00211] Similarly, in some embodiments, the method of stabilizing an active agent provides an active agent assay of 98% or more, 98.5%> or more, 99% or more, or 99.5% or more, of the active agent after the composition comprising one or more active agents and an alkylated cyclodextrin composition comprising an alkylated cyclodextrin and less than 500 ppm of a phosphate be maintained at a temperature of 80 ° C for a period of 120 minutes.

[00212] In some embodiments, the stabilization method provides an alkylated cyclodextrin composition comprising an alkylated cyclodextrin with a phosphate level of less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 125 ppm , less than 100 ppm, less than 75 ppm, or less than 50 ppm.

[00213] In some embodiments, the stabilization method provides an alkylated cyclodextrin composition comprising an alkylated cyclodextrin in which the alkylated cyclodextrin composition has an absorption of 0.5 A.U. or less, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution in a cell having a path length of 1 cm. In some embodiments, said absorption of 0.5 A.U. or less is due to a drug-degrading agent.

[00214] In general, alkylated cyclodextrin is present in an amount sufficient to stabilize the active agent. A sufficient amount can be a molar ratio of 0.1: 1 to 10: 1, 0.5: 1 to 10: 1, 0.8: 1 to 10: 1, or 1: 1 to 5: 1 (alkylated cyclodextrin : active agent).

[00215] A cyclodextrin in the combination composition does not need to bind with another material, such as an active agent, present in a formulation containing the same. However, if a cyclodextrin bonds with another material, such as a bond, it can be formed as a result of an inclusion complexation, an ion pair formation, a hydrogen bond, and / or a Van der Waals interaction.

[00216] An anionic derivatized cyclodextrin can complex, or otherwise bind with an acidic ionizable agent. As used herein, the term acid ionizable agent is taken to mean any compound that becomes or is ionized in the presence of an acid. An acidic ionizable agent comprises at least one acidic ionizable functional group that becomes ionized when exposed to an acid, or when placed in an acidic medium. Exemplary acid ionizable functional groups include a primary amine, a secondary amine, a tertiary amine, a quaternary amine, an aromatic amine, an unsaturated amine, a primary thiol, a secondary thiol, sulfonium, hydroxyl, enol, and others known to those skilled in the art. on the subject.

[00217] The degree to which an acid ionizable agent is bound by non-covalent ionic bonding, versus formation of inclusion complexation, can be determined spectrometrically using methods such as 1MR, 13C-NMR, or circular dichroism, for example, and by analysis of the phase solubility data for the acid ionizable agent and anionic derivatized cyclodextrin. The person skilled in the art will be able to use these conventional methods to approximate the amount of each type of bond that is occurring in the solution to determine whether or not the bond between species is occurring predominantly by non-covalent ionic bonding, or formation of inclusion complex . Under conditions where non-covalent ionic bond predominates over inclusion complex formation, the amount of inclusion complex formation, as measured by NMR or circular dichroism, will be reduced, even though phase solubility data indicates significant link between species under those conditions; in addition, the intrinsic solubility of the acid ionizable agent, as determined from the phase solubility data, will generally be higher than expected under those conditions.

[00218] As used herein, the term "non-covalent ionic bond" refers to a bond formed between an anionic species and a cationic species. A bond is non-covalent such that the two species together form a salt or ion pair. An anionic derivatized cyclodextrin provides the anionic species of the ion pair, and the acid ionizable agent provides the cationic species of the ion pair. Since an anionic derivatized cyclodextrin is multivalent, an alkylated cyclodextrin can form an ion pair with one or more ionizable acidic agents or, otherwise, cationic agents.

[00219] A liquid formulation of the invention can be converted to a solid formulation for reconstitution. A solid reconstitutable composition according to the invention comprises an active agent, a derivatized cyclodextrin and, optionally, at least one other pharmaceutical excipient. A reconstitutable composition can be reconstituted with an aqueous liquid to form a preserved liquid formulation. The composition can comprise a mixture (minimal no inclusion complex) of a solid derivatized cyclodextrin and a solid containing active agent and, optionally, at least one solid pharmaceutical excipient, such that a larger portion of the active agent is not complexed derivatized cyclodextrin before reconstitution. Alternatively, the composition can comprise a solid mixture of a derivatized cyclodextrin and an active agent, in which a larger portion of the active agent is complexed with the derivatized cyclodextrin before reconstitution. A solid reconstitutable composition can also comprise a derivatized cyclodextrin and an active agent where substantially all or at least a larger portion of the active agent is complexed with the derivatized cyclodextrin.

[00220] A reconstitutable solid composition can be prepared according to any of the following processes. A liquid formulation of the invention is first prepared, then a solid is formed by freeze drying (freeze drying), spray drying, freeze spray drying, solvent anti-precipitation, aseptic spray drying, various processes that use supercritical or almost fluids supercritical, or other methods known to those skilled in the art to produce a solid for reconstitution.

[00221] A liquid carrier included in a formulation of the invention can comprise an aqueous liquid carrier (e.g., water), an aqueous alcohol, an aqueous organic solvent, a non-liquid aqueous carrier, and combinations thereof.

[00222] The formulation of the present invention can include one or more pharmaceutical excipients, such as a conventional preservative, antifoaming agent, antioxidant, buffering agent, acidifying agent, alkalizing agent, bulking agent, dye, complexing intensifying agent , cryoprotectant, electrolyte, glucose, emulsifying agent, oil, plasticizer, solubility enhancing agent, stabilizer, tonicity modifier, flavorings, sweeteners, adsorbents, non-stick, binder, diluent, direct compression excipient, disintegrant, sliding agent, lubricant, opaque, polishing agent, complexing agents, fragrances, other excipients known to those skilled in the art for use in formulations, combinations thereof.

[00223] As used herein, the term "adsorbent" is intended to mean an agent capable of retaining other molecules on its surface by physical or chemical means (chemosorption). Such compounds include, by way of example and without limitation, powdered and activated charcoal, and other materials known to a person skilled in the art.

[00224] As used herein, the term "alkalizing agent" is intended to mean a compound used to provide alkaline medium for the stability of the product. Such compounds include, by way of example and without limitation, ammonia solution, ammonia carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, diethanolamine, amine base organic, alkaline amino acids, and trolamine, and others known to those skilled in the art.

[00225] As used herein, the term "acidifying agent" is intended to mean a compound used to provide an acidic medium for the stability of the product. Such compounds include, by way of example and without limitation, acetic acid, amino acids, citric acid, fumaric acid and other α-hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid, and others known to those skilled in the art.

[00226] As used herein, the term "non-stick" is intended to mean an agent that prevents the stickiness of solid dosage formulation ingredients from punctures and molds in a tabletting machine during production. Such compounds include, by way of example and without limitation, magnesium stearate, talc, calcium stearate, glyceryl behenate, polyethylene glycol, hydrogenated vegetable oil, mineral oil, stearic acid, and other materials known to a person skilled in the art.

[00227] As used herein, the term "binder" is intended to mean a substance used to cause adhesion of powder particles in solid dosage formulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, sodium carboxymethyl cellulose, poly (vinylpyrrolidone), compressible sugar, ethyl cellulose, gelatin, liquid glucose, methyl cellulose, povidone, and pregelatinized starch, and other known materials to a technician on the subject.

[00228] When necessary, binders can also be included in the dosage forms. Exemplary binders include acacia, tragacanth, starch, cellulose materials, such as methyl cellulose and sodium carboxymethylcellulose, alginic acids, and salts thereof, polyethylene glycol, guar gum, polysaccharides, bentonites, sugars, inverted sugars, poloxamers (PLURONIC ™ F68 , PLURONIC ™ F127), collagen, albumin, gelatin, cellulose in non-aqueous solvents, combinations of these, and others known to those skilled in the art. Other binders include, for example, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, combinations thereof, and other materials known to a person skilled in the art.

[00229] As used herein, a conventional preservative is a compound used to at least reduce the rate at which the biocharge increases, but keeps the biocharge constant, or reduces the biocharge after contamination. Such compounds include, by way of example and without limitation, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, metacresol, myristylgamine picolinium chloride , potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thymol, and methyl, ethyl, propyl or butyl parabens, and others known to those skilled in the art. It is understood that some preservatives can interact with the alkylated cyclodextrin thereby reducing the efficiency of the preservative. However, by adjusting the choice of preservative and concentrations, adequately preserved alkylated cyclodextrin formulations can be found.

[00230] As used herein, the term "diluent" or "filler" is intended to mean an inert substance used as a filler to create the desired mass, flow properties, and compression characteristics, in the preparation of a liquid dosage form or solid. Such compounds include, by way of example and without limitation, a liquid carrier (e.g., water, alcohol, solvents, and the like), dibasic calcium phosphate, kaolin, lactose, dextrose, magnesium carbonate, sucrose, mannitol, microcrystalline cellulose , powdered cellulose, precipitated calcium carbonate, sorbitol, and starch, and other materials known to a person skilled in the art.

[00231] As used herein, the term "direct compression excipient" is intended to mean a compound used in compressed solid dosage forms. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, and other materials known to a person skilled in the art.

[00232] As used herein, the term "antioxidant" is intended to mean an agent that inhibits oxidation and is thus used to prevent deterioration of preparations by the oxidizing process. Such compounds include, by way of example and without limitation, acetone, potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl galate, sodium ascorbate, citrate sodium, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, EDTA, pentetate, and sodium metabisulfite, and others known to those skilled in the art.

[00233] As used herein, the term "buffering agent" is intended to mean a compound used to resist change in pH after dilution or addition of acid or alkali. Such compounds include, by way of example and without limitation, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, monobasic sodium phosphate, phosphatododiodiodibasic , 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid, lactic acid, tartaric acid, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium bicarbonate, tris, sodium tartrate, and anhydrous sodium citrate, and dihydrate , and others known to those skilled in the art.

[00234] A complexing enhancing agent can be added to a formulation of the invention. When such an agent is present, the cyclodextrin / active agent ratio can be changed. A complexation-enhancing agent is a compound, or compounds, that intensifies (m) the complexation of the active agent with cyclodextrin. Suitable complexing enhancing agents include one or more pharmacologically inert water-soluble polymers, hydroxy acids, and other organic compounds typically used in preserved formulations to enhance the complexation of a particular agent with cyclodextrins.

[00235] Hydrophilic polymers can be used as water-reducing agents to intensify complexation, to enhance solubility, and / or to reduce activity, to improve the performance of formulations containing a preservative based on CD. Loftsson revealed a number of polymers suitable for use combined with a cyclodextrin (non-derivatized or derivatized) to enhance the performance and / or properties of the cyclodextrin. Suitable polymers are disclosed in Pharmazie 56: 746 (2001); J. Pharm. 212: 29 (2001); Cyclodextrin: From Basic Research to Market, 10th Int'l Cyclodextrin Symposium, Ann Arbor, MI, US, May 21-24, p. 1015 (2000); PCT Int'l Pub. No. WO 99/42111; Pharmazie 55: 733 (1998); Pharm. Technol. Eur. 9:26 (1997); J. Pharm. Sci. 85: 1017 (1996); European Patent Application. No. 0 579 435; Proc. of the 9th Int'l Symposium on Cyclodextrins, Santiago de Comostela, ES, May 31-June 3, 1998, pp. 261-264 (1999); S.T.P. Pharma Sciences 9: 237 (1999); Amer. Chem. Soc. Symposium Series 737 (Polysaccharide Applications): 24-45 (1999); Pharma. Res. 15: 1696 (1998); Drug Dev. Ind. Pharm. 24: 365 (1998); J. Pharm. 163: 115 (1998); Book of Abstracts, 216th Amer. Chem. Soc. Nat'l Meeting, Boston, Aug. 23-27 CELL-016 (1998); J. Controlled Release 44:95 (1997); Pharm. Res. (1997) 14 (11), S203; Invest. Ophthalmol. Vis. Sci. 37: 1199 (1996); Proc. of the 23rd Int'l Symposium on Controlled Release of Bioactive Materials 453-454 (1996); Drug Dev. Ind. Pharm. 22: 401 (1996); Proc. of the 8th Int'l Symposium on Cyclodextrins, Budapest, HU, Mar. 31-Apr. 2, 1996, pp. 373-376 (1996); Pharma. Sci. 2: 277 (1996); Eur. J. Pharm. Sci. 4SS144 (1996); 3rd Eur. Congress of Pharma. Sci. Edinburgh, Scotland, UK September 15-17, 1996; Pharmazie 51:39 (1996); Eur. J. Pharm. Sci. 4SS143 (1996); United States Patents Nos. 5,472,954 and 5,324,718; J. Pharm. 126: 73 (1995); Abstracts of Papers of the Amer. Chem. Soc. 209: 33-CELL (1995); Eur. J. Pharm. Sci. 2: 297 (1994); Pharm. Res. II: S225 (1994); J. Pharm. 704: 181 (1994); and Int. J. Pharm. 110: 169 (1994), the total revelations of which are thus incorporated by reference in their entirety.

[00236] Other suitable polymers are well-known excipients commonly used in the field of pharmaceutical formulations, and are included in, for example, Remington's Pharmaceutical Sciences, 18th ed., Pp. 291-294, A.R. Gennaro (editor), Mack Publishing Co., Easton, PA (1990); A. Martin et ah, Physical Pharmacy. Physical Chemical Principles in Pharmaceutical Sciences, 3d ed., Pp. 592-638 (Lea & Febinger, Philadelphia, PA (1983); AT Florence et ah, Physico-chemical Principles of Pharmacy, 2d ed., Pp. 281334, MacMillan Press, London, UK (1988), the revelations of which are, of this thus, incorporated by reference in their entirety. Still other suitable polymers include natural water-soluble polymers, synthetic water-soluble polymers (such as water-soluble cellulose derivatives) and synthetic water-soluble polymers. Natural polymers include polysaccharides, such such as inulin, pectin, algin derivatives (eg, sodium alginate) and agar, and polypeptides, such as casein and gelatin. Semi-synthetic polymers include cellulose derivatives, such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, their mixed ethers, such as hydroxypropylmethylcellulose and other mixed ethers, such as hydroxyethylethylcellulose and hydroxypropylethylcellulose, hydroxypropylmethylcellulose phthalate and carboxymethylcellulose and its salts, especially sodium carboxymethylcellulose. Synthetic polymers include polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrene sulfonate), and various acrylic acid copolymers (for example carbomer). Other natural synthetic and semi-synthetic polymers not named here that meet the criteria of water solubility, pharmaceutical acceptability and pharmacological inactivity are likewise considered to be within the scope of the present invention.

[00237] As used herein, a fragrance is a relatively volatile substance, or combination of substances that produce a detectable aroma, odor or scent. Exemplary fragrances include those generally accepted as safe by the United States Food and Drug Administration.

[00238] As used herein, the term "sliding agent" is intended to mean an agent used in solid dosage formulations to promote solid mass flowability. Such compounds include, by way of example and without limitation, colloidal silica, corn starch, talc, calcium silicate, magnesium silicate, colloidal silicone, tribasic calcium phosphate, silicone hydrogel, and other materials known to a person skilled in the art. .

[00239] As used herein, the term "lubricant" is intended to mean a substance used in solid dosage formulations to reduce friction during compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, polyethylene glycol, talc, mineral oil, stearic acid, and zinc stearate, and other materials known to a person skilled in the art.

[00240] As used herein, the term "opaque" is intended to mean a compound used to make a coating opaque. An opaque can be used alone or in combination with a dye. Such compounds include, by way of example and without limitation, titanium dioxide, talc, and other materials known to a person skilled in the art.

[00241] As used herein, the term "polishing agent" is intended to mean a compound used to impart an attractive shine to solid dosage forms. Such compounds include, by way of example and without limitation, carnauba wax, white wax, and other materials known to a person skilled in the art.

[00242] As used herein, the term "disintegrant" is intended to mean a compound used in solid dosage forms to promote the breakdown of the solid mass into smaller particles that are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, bentonite, microcrystalline cellulose (eg AviCEL®), calcium carboxymethylcellulose , croscarmellose sodium, alginic acid, sodium alginate, cellulose polacriline potassium (eg, AMBERLITE®), alginates, sodium starch glycolate, gums, agar, guar, carob, karaya gum, pectin, tragacanth, crospovidone, and other materials known to a technician on the subject.

[00243] As used herein, the term "stabilizer" is intended to mean a compound used to stabilize the therapeutic agent against a physical, chemical, or biochemical process, which would reduce the therapeutic activity of the agent. Suitable stabilizers include, by way of example and without limitation, albumin, sialic acid, creatinine, glycine, and other amino acids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycols , sodium caprylate, and sodium saccharin, and others known to those skilled in the art.

[00244] As used herein, the term "tonicity modifier" is intended to mean a compound or compounds that can be used to adjust the tonicity of the liquid formulation. Tonicity modifiers include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose, and others known to those skilled in the art. In some embodiments, the tonicity of the liquid formulation approximates the tonicity of the blood or plasma.

[00245] As used herein, the term "defoaming agent" is intended to mean a compound or compounds that prevent or reduce the amount of skimming that forms on the surface of the liquid formulation. Suitable antifoaming agents include dimethicone, simethicone, octoxynol, and others known to those skilled in the art.

[00246] As used herein, the term "bulking agent" is intended to mean a compound used to add mass to the solid product and / or assist in controlling the properties of the formulation during lyophilization. Such compounds include, by way of example and without limitation, dextran, trehalose, sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol, dimethylsulfoxide, glycerol, albumin, calcium lactobionate, and others known to those skilled in the art.

[00247] As used herein, the term "cryoprotectant" is intended to mean a compound used to protect an active therapeutic agent from physical or chemical degradation during lyophilization. Such compounds include, by way of example and without limitation, dimethyl sulfoxide, glycerol, trehalose, propylene glycol, polyethylene glycol, and others known to those skilled in the art.

[00248] As used herein, the term "emulsifier" or "emulsifying agent" is intended to mean a compound added to one or more of the phase components of an emulsion for the purpose of stabilizing the droplets of the internal phase within the external phase . Such compounds include, by way of example and without limitation, lecithin, polyoxyethylene-polyoxypropylene ethers, polyoxyethylene-sorbitan monolaurate, polysorbates, sorbitan esters, stearyl alcohol, tiloxapol, tragacanth, xanthan gum, acacia, agar, alginic acid, sodium alginate, sodium alginate, bentonite, carbomer, sodium carboxymethyl cellulose, cholesterol, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, octoxynol, oleyl alcohol, polyvinyl alcohol, povidone, propylene glycol monostearate, sodium lauryl sulfate, and others known to those skilled in the art.

[00249] A solubility-enhancing agent can be added to the formulation of the invention. A solubility-enhancing agent is a compound, or compounds, that enhances the solubility of the active agent when in a liquid formulation. When such an agent is present, the cyclodextrin / active agent ratio can be changed. Suitable solubility-enhancing agents include one or more organic solvents, detergents, soaps, surfactants, and other organic compounds typically used in parenteral formulations to enhance the solubility of a particular agent.

Suitable organic solvents include, for example, ethanol, glycerin, polyethylene glycols, propylene glycol, poloxomers, and others known to those skilled in the art.

[00251] Formulations comprising the alkylated cyclodextrin composition of the invention may include oils (e.g., fixed oils, peanut oil, sesame oil, cottonseed oil, corn oil, olive oil, and the like), acids fatty acids (e.g., oleic acid, stearic acid, isostearic acid, and the like), fatty acid esters (e.g., ethyl oleate, isopropyl myristate, and the like), fatty acid glycerides, acetylated fatty acid glycerides, and combinations of these . Formulations comprising the alkylated cyclodextrin composition of the invention can also include alcohols (for example, ethanol, iso-propanol, hexadecyl alcohol, glycerol, propylene glycol, and the like), glycerol ketals (for example, 2,2-dimethyl-1, 3-dioxolane-4-methanol, and the like), ethers (for example, poly (ethylene glycol) 450, and the like), petroleum hydrocarbons (for example, mineral oil, petrolatum, and the like), water, surfactants, suspension, emulsifying agents, and combinations thereof.

[00252] It should be understood that the compounds used in the pharmaceutical formulation technique generally serve a variety of functions or proposals. Thus, if a compound named here is mentioned only once, or is used to define more than one term here, its proposal or function should not be construed as being limited to only that proposal (s) or function (s) ).

[00253] Formulations comprising the alkylated cyclodextrin composition of the invention may also include biological salt (s), sodium chloride, potassium chloride, and other electrolyte (s).

[00254] Since some active agents are subjected to oxidative degradation, a liquid formulation, according to the invention, can be substantially free of oxygen. For example, the free space of a container containing a liquid formulation can produce free oxygen, substantially free oxygen, or reduced oxygen by purging the free space with an inert gas (for example, nitrogen, argon, carbon dioxide, and the like), or by bubbling an inert gas through a liquid formulation. For long-term storage, a liquid formulation containing an active agent subjected to oxidative degradation can be stored in an oxygen-free or oxygen-reduced environment. The removal of oxygen from the formulation will enhance the preservation of the formulation against aerobic microbes; so the addition of oxygen to the formulation will enhance preservation against anaerobic microbes.

[00255] The phrase "pharmaceutically acceptable" is used here to refer to those compounds, materials, compositions, and / or dosage forms that are within the scope of the invention, suitable for use without contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[00256] As used herein, the term "patient" or "individual" is taken to mean warm-blooded animals, such as cats, dogs, mice, guinea pigs, horses, cows, sheep, other animals, and beings humans.

[00257] A formulation of the invention will comprise an active agent present in an effective amount. By the term "effective amount," the amount or amount of active agent that is sufficient to induce the required or desired response is significant, or, in other words, the amount that is sufficient to induce an appreciable biological response when administered to an individual.

[00258] The compositions of the present invention may be present in formulations for dosage forms, such as a reconstitutable solid, tablet, capsule, pill, plaster, osmotic device, suppository, implant, gum, effervescent composition, injectable liquid, ophthalmic solutions or nasal, or inhalable powders, or solutions.

The invention also provides methods of preparing a liquid formulation comprising one or more active agents and an alkylated cyclodextrin composition, in which the alkylated cyclodextrin composition comprises an alkylated cyclodextrin and less than 500 ppm of a phosphate. A first method comprises: forming a first aqueous solution comprising an alkylated cyclodextrin composition; forming a second solution or suspension comprising one or more active agents; and mixing the first and second solutions to form a liquid formulation. A second similar method comprises adding one or more active agents directly to a first solution without forming the second solution. A third method comprises adding a directly alkylated cyclodextrin composition to a solution / suspension containing one or more active agents. A fourth method comprises adding a solution comprising one or more active agents to a powdered or particulate alkylated cyclodextrin composition. A fifth method comprises adding one or more active agents directly to a powdered or particulate alkylated cyclodextrin composition, and adding the resulting mixture to a second solution. A sixth method comprises creating a liquid formulation by any of the above methods and then isolating a solid material by lyophilization, spray drying, aseptic spray drying, freeze spray drying, solvent anti-precipitation, a process using a supercritical fluid or almost supercritical, or any method known to those skilled in the art to produce a powder for reconstitution.

[00260] Specific embodiments of the methods of preparing a liquid formulation include those in which: 1) the method further comprises sterile filtration of the formulation using a filtration medium having a pore size of 0.1 µm or greater; 2) the liquid formulation is sterilized by irradiation or autoclaving; 3) the method further comprises isolating a solid form from the solution; 4) the solution is purged with nitrogen or argon, or another pharmaceutically inert acceptable gas, such that a substantial portion of the oxygen dissolved in, and / or in surface contact with, the solution is removed.

[00261] The invention also provides a solid reconstitutable pharmaceutical composition comprising one or more active agents, an alkylated cyclodextrin composition and, optionally, at least one other pharmaceutical excipient. When this composition is reconstituted with an aqueous liquid to form a preserved liquid formulation, it can be administered by injection, infusion, topically, by inhalation, or orally, to an individual.

[00262] Some embodiments of the reconstitutable solid pharmaceutical composition include those in which: 1) the pharmaceutical composition comprises a mixture of an alkylated cyclodextrin composition and a solid comprising one or more active agents and, optionally, at least one solid pharmaceutical excipient, such as that a larger portion of the active agent is not complexed with an alkylated cyclodextrin before reconstitution; and / or 2) the composition comprises a solid mixture of an alkylated cyclodextrin composition and one or more active agents, in which a larger portion of the one or more active agents is complexed with the alkylated cyclodextrin before reconstitution.

[00263] A composition of the invention can be used in a pharmaceutical dosage form, pharmaceutical composition, or other such combination of materials. These alkylated cyclodextrin compositions are also useful as, but not limited to, analytical reagents, food and cosmetic adjuvants and / or additives, and as environmental cleansing agents.

[00264] In view of the description above and the examples below, a person skilled in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions, and formulations according to the present invention. All references made to these examples are for the purpose of illustration. The following examples are not to be considered exhaustive, but merely illustrative of only a few of the many embodiments contemplated by the present invention.

EXAMPLES EXAMPLE 1 Determination of Active Agent Solubility

[00265] The comparative assessment of the solubilization effect of various sulfoalkyl ether cyclodextrin compositions on pharmaceutical active agents was determined as follows. 0.04 M stock solutions of each selected cyclodextrin were prepared with purified water. The clarity of the solutions was determined by visual inspection, or instrumentally. A clear solution is at least clear by visual inspection with the naked eye. Each pharmaceutical active agent, tested in duplicate, was combined with 2 ml or 4 ml of an aqueous solution of SAE-CD.

[00266] The active pharmaceutical agents were weighed in quantities in excess of their anticipated solubility, and placed in TEFLON®-coated flasks with a screw cap. The active agents were present in amounts of at least 3 mg / ml. Each vial was then filled with the appropriate amount of cyclodextrin solution (either 2 ml or 4 ml). The vials were centrifuged and sonicated to help wet the solids with the fluid. The flasks were then placed in a lab quake or cylinder mixer for equilibration. Weakers were visually inspected periodically to ensure that the solids were properly wetted and in contact with the fluid. The fluid inside the flasks was then periodically sampled to determine the concentration of active pharmaceutical agent present in the solution. Samples were typically measured at 24 hour intervals.

[00267] The sampling of the vials to determine the solubility of the active agent was carried out by decanting 1 ml of solution from the vial, followed by additional centrifugation. The removed supernatant was then filtered using a 0.22 μm syringe filter, and diluted with the mobile phase to an appropriate concentration within the standard curve. The samples were then analyzed by HPLC to determine the concentration of the solubilized drug derivatives.

EXAMPLE 2 Determination of Moisture Content

[00268] The following procedure was used to assess the moisture content of the alkylated cyclodextrins. Determinations were performed in duplicate on 250 mg each using a Brinkman Karl-Fischer Coulometer (Brinkman Instruments Co., IL). A known weight of solid cyclodextrin was added to the Karl-Fischer Coulometer, and the total amount of water in the sample is measured. The total amount of water present is then converted to a percentage of the solid to give the percentage of moisture content in the sample.

EXAMPLE 3 Capillary Electrophoresis Analysis

[00269] The following procedure was used to analyze compositions derived from SAE-CD by capillary electrophoresis. A Beckman P / ACE 2210 capillary electrophoresis system coupled with a UV absorbance detector (Beckman Instruments, Inc., Fullereton, CA) was used to analyze the SBE-β-CD and SBE-Y-CD derivative solutions. The separations were carried out at 25 ° C using a fused silica capillary (having an internal diameter of 50 μm, a total length of 57 cm, and an effective length of 50 cm) with an operating buffer adjusted to a pH of 30 mM of benzoic acid and 100 mM TRIS (tris-hydroxymethyl-aminomethanol).

[00270] The capillary was treated with the following washing sequence before each injection:

[00271] water, 0.01 N NaOH, and operation buffer. The detector was set at 214 nm. The voltage was 30 kV. The samples were introduced by pressure injections: 20 seconds at 0.5 psi.

EXAMPLE 4

[00272] An α-CD-derived composition having a monomodal distribution profile can be prepared according to Example 5, or any of the methods in the literature cited here, except that α-CD would be used in place of β-CD or Y-CD. An exemplary SBE-α-CD is produced using the following procedure, in which an α-cyclodextrin in an alkaline aqueous medium is derivatized with an SBE precursor to form the SBE-α-CD. Α-CD is dissolved in aqueous NaOH solution, heated to 70 ° C, and stirred until complete dissolution. Once the dissolution is complete, the reaction temperature is increased to between 70 ° C to 75 ° C.

[00273] Then 1,4-butanesultone was added for a period of at least 30 minutes. The pH is monitored during the first 4 hours, and the reaction is allowed to continue at 70 ° C for at least an additional 16 hours. The reaction mixture is cooled and diluted with water (roughly one third of the total reaction volume). The solution is additionally treated with carbon (0.07 grams of carbon / gram of cyclodextrin), neutralized with HCl at pH 6-6.5, and filtered through a 0.45 μm filter. The solution is purified by ultrafiltration using a 650 MWCO membrane. The ultrafiltration end point is determined by capillary electrophoresis in which the filtrate showed or substantially did not show the presence of 4-hydroxybutane-l-sulfonic acid and / or disodium bis (4-sulfobutyl) ether, and by osmolarity, in which the samples permeate have little to no ions present. The solution is filtered through a 0.22 μm filter and neutralized (pH 6-6.5). The resulting solution is concentrated to roughly 50% solution by rotary evaporation at between 50 ° C to 60 ° C under less than a vacuum at 30 mmHg. The solution is lyophilized to produce a white SBE-α-CD solid.

EXAMPLE 5 Synthesis of SBE6.6-β-CD

[00274] A composition of SBE6.6-β-CD was synthesized according to the following procedure, in which a β-cyclodextrin in an alkaline aqueous medium was derivatized with an SBE precursor to form SBE6.6-β-CD . An aqueous solution of sodium hydroxide was prepared by loading 61.8 kg of sodium hydroxide to 433 kg of water to 12.5% w / w of solution. The contents of the reactor were heated to between 40 ° C and 50 ° C before the beginning of the addition of 270 kg of β-CD for 30 to 60 minutes. The reaction temperature was adjusted to between 65 ° C to 95 ° C before adding 259 kg of 1,4-butane sultone for 30 to 60 minutes. After 6 hours, the pH of the solution was maintained above 9 using an aqueous sodium hydroxide solution. Following the reaction, an additional 13.5 kg of sodium hydroxide as a 20% solution was charged to the reaction. The contents were maintained at between 70 ° C to 80 ° C until the residual level of 1,4-butane sultone was sufficiently low. The contents were cooled to less than 30 ° C, and the reaction solution was adjusted to pH 6.5-7.5 with aqueous hydrochloric acid solution. This process produced 350 to 450 kg of SAE-CD.

EXAMPLE 6 Diafiltration and Ultrafiltration of SBEβ 6.6-β-CD

[00275] The SBE6.6-β-CD of Example 5 was purified by the following procedure. The reaction solution was diluted with 800 kg of water. The solution was transferred and further diluted with 500 kg of water. Diafiltration was initiated using a Millipore Helicon Automatic Ultrafiltration System using 1000 MWCO spiral wound regenerated cellulose membranes having at least 750 feet of membrane area and maintaining a constant volume of solution (± 1%) until a sample of the returnee has 25 ppm or less of sodium chloride. The solution was concentrated by ultrafiltration until an appropriate solution mass was reached.

EXAMPLE 7 Carbon Processing of SBE66-β-CD of the present invention

[00276] Following diafiltration and ultrafiltration in Example 6, SBE6.6-β-CD was purified by carbon by the following procedure. A column was loaded with 32 kg (about 11-12% by weight (11.812% by weight) of the starting quantity of β-cyclodextrin) of granular activated carbon of SHIRASAGI® DC32, and washed thoroughly with water until the samples of washings have a constant conductivity. The ratio of SBE6.6-β-CD to activated carbon was about 8.4: 1 to 8.5: 1 (about 8.44: 1). Once washed, the reaction solution was passed (recycled) through the carbon for at least 2 hours to complete a first treatment cycle.

[00277] A second column was loaded with 32 kg (about 1112%) by weight of the starting amount of granular activated carbon β-cyclodextrin) of SHIRASAGIR DC32, and washed thoroughly with water until the washing samples have a conductivity constant. Once washed, the reaction solution was passed through the carbon for at least 2 hours to complete a second treatment cycle.

EXAMPLE 8 Concentration and Isolation of SBE6-6-β-CD

[00278] The carbon-treated SBE6-6-β-CD solutions prepared in Example 7 were concentrated and isolated using the following procedure: a SBE6-6-β-CD solution was filtered through 0.65 μm filters and 0.22 μm and then concentrated at a reduced pressure of -0.6 bar to -0.7 bar at a temperature of 65 ° C to 72 ° C, with agitation at 70 rpm at 100 rpm, until a solution having a SBE6.6-β-CD concentration of 50% w / w was achieved. The concentrated solution was cooled to below 60 ° C, and then filtered through 0.65 μm and 0.22 μm filters. The filtered solution was then spray dried using a fluidized spray dryer ("FSD") system at an inlet temperature of 170 ° C, an initial pressure of 20 bar, and chambers 1-3 having set points 125 ° C, 105 ° C, and 100 ° C, respectively.

EXAMPLE 9 Determination of the replacement pattern of Cyclodextrin 1H-NMR, 13C-NMR, COZY-NMR and HMQC in a Bruker AVANCE® 400 or 500 instrument in D2O solutions

[00279] The determination of the substitution pattern is conducted according to the method of Example 6 of WO 2005/042584, the relevant disclosures of which are thus incorporated herein.

EXAMPLE 10 Comparative Carbon Processing of SBE6-6-β-CD

[00280] An exemplary SBE6.6-β-CD was purified by carbon by the following procedure: a column was loaded with 32 kg (about 11-12% by weight (11.8-12% by weight) of the starting amount of β-cyclodextrin in Example 5) of granular activated carbon of SHIRASAGIR DC32, and washed thoroughly with water until the wash samples have a constant conductivity. Once washed, the reaction solution was passed through carbon for at least 2 hours.

EXAMPLE 11 Impurity Analysis I of SBE6-6-β-CD

[00281] Samples of SBE6-6-β-CD treated either once or twice with activated carbon according to Examples 10 and 7, respectively, concentrated and isolated by the process described in Example 8, were then analyzed by UV / vis spectrophotometry. The analysis was performed by dissolving an appropriate amount of SBE6-6-β-CD in water (for example, 0.1 g to 6 g of SBE6.6-β-CD, corrected for water content, dissolved in 10 mL of water) to provide solutions containing 1% to 60% w / w derivatized cyclodextrin.

[00282] Carbon-treated cyclodextrin solutions were analyzed on a Perkin Elmer Lambda 35 UV / Vis spectrophotometer, which scans from 190 nm to 400 nm at a speed of 240 nm / min and a slit width of 1.0 nm . The samples were covered with water before analysis. The UV / vis absorption spectrum of various concentrations of SBE6-6-β-CD solutions after one and two activated carbon treatments is provided graphically in FIGs. 1 and 2, respectively, which provide a graphical representation of the batches of SBE6-6-β-CD after one or two carbon treatments analyzed by the UV method. Referring to FIG. 1, the data shows that a higher concentration shows that a higher concentration of impurities having an absorption in the UV / visible region of the spectrum is present when a solution of SBE6-6-β-CD is treated only once with activated carbon . Referring to FIG. 2, the data shows that a second carbon treatment reduces the level of UV / vis absorption impurities at least five times or more.

EXAMPLE 12 Impurity Analysis II of SBE6-6-β-CD

[00283] An exemplary sample of SBE6-6-β-CD was analyzed by UV / vis spectrophotometry using the following procedure: a 50% w / w solution of SBE6.6-β-CD was prepared by dissolving 54.1 grams of SBE6.6-β-CD, corrected for water content, in a caustic solution of 12.5 grams of sodium hydroxide in 100 mL of water. The initial solution was analyzed on a PERKIN ELMER Lambda 35 UV spectrophotometer, which scans from 190 nm to 400 nm at a speed of 240 nm / min and a slit width of 1.0 nm. The sample was covered with water before analysis. The solution was placed in an oven at 60 ° C for up to 168 hours. The solution samples were analyzed at 24 hours, 72 hours, 96 hours, and 168 hours.

[00284] FIG. 3 provides a graphical representation of the results from thermal and caustic stress in SBE6.6-β-CD compositions. Referring to FIG. 3, the data shows that within 24 hours, a significant absorption at a wavelength from 245 nm to 270 nm has formed, and that this absorption increases with the duration of thermal and caustic exposure. For 168 hours (7 days), the maximum absorption at a wavelength of 245 nm to 270 nm increased to an equal magnitude with the absorption having a maximum at about 230 nm. Also of note is that the absorption at a wavelength of 320 nm to 350 nm also increases with the exposure time. The data shows that a drug degradation impurity having an absorption at a wavelength of 245 nm to 270 nm, as well as a heat forming agent having an absorption at a wavelength of 320 nm to 350 nm, increases by concentration over time under exposure to heat and / or caustic conditions.

EXAMPLE 13 Measurements of color forming agents

[00285] SBE6-6-β-CD compositions that support single or double treatment with activated carbon (according to Examples 10 and 7, respectively) were formulated with an antifungal API triazole (posaconazole, which was purchased from Schering- Plow as an aqueous oral suspension, NOXAFIL®). The formulation procedure is provided below.

Análise de Cor de Solução de SBE6-6-β-CD

[00286] Samples of aqueous solution of an antifungal API triazole (5 mg / mL) and a SBE6.6-β-CD composition (100 mM, pH 3) were prepared using SBE6.6-β-CD Lots Nos. 17CX01.HQ00044, 17CX01.HQ00037,17CX01.HQ00035,17CX01.HQ00033, e17CX01.HQ00029. All solution samples were filtered through a 0.22 μm PVDF filter, and separated into flasks. The UV / Vis absorption of a portion of the initial solutions was measured using a 1 cm Hunter vat on a PERKIN ELMER Lambda 35 UV / Vis spectrophotometer, which scans from 190 nm to 400 nm at a speed of 240 nm / min and a slit width of 1.0 nm, and analyzed in a Hunter Labs ULTRASCANR colorimeter using Hunter Labs universal software, version 4.10. The samples were covered with water before measurement. The remaining portions of samples were then placed in an oven at 60 ° C for 7 days and then re-analyzed for color changes using the same procedure. The data is shown in the following tables. Initial solutions of SBE6-6-β-CD: UV / Vis analysis

Color Analysis of SBE6-6-β-CD Solution

[00287] L = clarity; 100 for perfect white and 0 for black;

L = claridade; 100 para branco perfeito e 0 para negro;a= mede vermelhidão quando positivo, cinza quando zero, e esverdeado quando negativo; b = mede amarelado quando positivo, cinza quando zero, e azulado quando negativo; DE= Diferenças Totais V( AL2 + Aa2 + Ab2) a partir do Padrão.[00288] a = measures redness when positive, gray when zero, and greenish when negative; b = yellow when positive, gray when zero, and bluish when negative; DE = Total Differences V (AL2 + Aa2 + Ab2) from the API / SBE6.6-β-CD Triazole Color Solution Analysis

L = clarity; 100 for perfect white and 0 for black, a = measures redness when positive, gray when zero, and greenish when negative; b = yellow when positive, gray when zero, and bluish when negative; DE = Total Differences V (AL2 + Aa2 + Ab2) from the Standard.

[00289] UV analysis demonstrated that the UV active impurities present in the initial composition of SBE6.6-β-CD are much lower when the cyclodextrin composition is treated twice with activated carbon. Hunter color analysis of the SBE6.6- β-CD composition indicated lower ED values for those batches of SBE6.6- β-CD that were processed using a dual activated carbon treatment. Thus, the lower levels of impurity in the composition of SBE6.6-β-CD, which was treated twice with activated carbon, resulted in reduced formation of color forming agents.

EXAMPLE 14 SBE6.6-β-CD subjected to heat following carbon treatment

[00290] The heating effect of a derivatized cyclodextrin composition of the present invention was studied as follows. The SBE6.6-β-CD composition prepared according to Example 5 was dissolved in an aqueous solution and analyzed using UV / vis spectrophotometry. Specifically, 30% w / w of β-cyclodextrin solution was prepared by dissolving 70 grams of SBE6.6-β-CD Lot No. 17CX01.HQ00044 (corrected for water content) in 230 mL of water. This initial solution was analyzed on a Perkin ELMER Lambda 35 UV / Vis spectrophotometer, which scans from 190 nm to 400 nm at a speed of 240 nm / min and a slit width of 1.0 nm. The sample was covered with water before analysis. The solution was heated with stirring at 70 ° C for 48 hours. The solution was cooled to room temperature and divided. To each of the divided solutions, pre-washed granular activated carbon SHIRASAGI® DC32 was added. The SBE6.6-β-CD solutions were stirred for 3 hours, and then the activated carbon was filtered using a 0.22 μm PVDF filter. The solutions were analyzed using a PERKIN ELMER Lambda 35 UV / Vis spectrophotometer, which scans from 190 nm to 400 nm at a speed of 240 nm / min and a slit width of 1.0 nm. The samples were covered with water before analysis.

[00291] The data is represented graphically in FIG. 4. Referring to FIG. 4, the UV / vis absorption of the solution before heat treatment (++++) immediately after 48 hours of heat treatment (■■■■), and after exposure to activated carbon at a loading of 0.24% w / p (••••••••), 10% w / w (), 25% w / w (♦♦♦♦), and 50% w / w (□□□□), (according to concentration of SBE66-β-CD), is provided. The data shows that the exposure of the SBE6.6-β-CD solution to heat for 48 hours resulted in a significant decrease (approximately 95%) in the maximum absorption at a wavelength from 245 nm to 270 nm. However, treatment with activated carbon decreases absorption in this wavelength range. In this way, the impurity of drug degradation having an absorption at a wavelength of 245 nm to 270 nm increases with heating, but can be removed through carbon treatment.

EXAMPLE 15 SBE6-6-β-CD stability and API

[00292] The comparative evaluation of several batches of SBE6.6-β-CD processed with a single or double carbon treatment with an antipsychotic API (aripiprazole) was examined by UV / vis spectrophotometry and HPLC analysis. The general procedure used to assess the stability of SBE6.6-β-CD / API formulations is provided below.

[00293] Aqueous solutions comprising API samples (aripiprazole) were prepared with an API concentration of 7.5 mg / ml and a SBE6.6-β-CD concentration of 150 mg / ml. Tartaric acid was added to the water until dissolved, and aSBE6.6-β-CD was then added to the tartaric acid solution. The API was then added to the solutions, and dissolved within about 10 minutes of the additions. The mixture was stirred for about 1 hour, heated, treated, and then filtered through a sterile filter. This process was carried out using the following lots of SBE6.6-β-CD, some of which support a single treatment with activated carbon, and others that support two treatments with activated carbon (SBE6.6-β-CD Lot Nos. 17CX01. HQ00021, 17CX01.HQ00035, 17CX01.HQ00038, 17CX01.HQ00041, 17CX01.HQ00044). The solution samples were placed in a stability chamber at 50 ° C for up to 9 weeks. The samples were removed at 4 weeks and again at 9 weeks, and HPLC analysis was performed to determine the extent of API degradation.

Análise de Impureza SAE-CD & API

[00294] The aqueous solution samples were analyzed by UV / vis spectrophotometry using the following procedure. 30% w / w β-cyclodextrin solution was prepared by dissolving the SBE6.6-β-CD lots above (corrected for water content) in water. The solution was analyzed in a 1 cm well using a PER / UV PERKIN ELMER Lambda 35 spectrophotometer, which scans from 190 nm to 400 nm at a speed of 240 nm / min and a slit width of 1.0 nm. The samples were covered with water before analysis. The following tables include data from this study. SBE6.6-β-CD Batch Summary and UV Content

Impurity Analysis SAE-CD & API

[00295] The data show that the API supports significantly higher degradation when it is formulated with a batch of SBE66- β-CD that only supported a single activated carbon treatment. The API formulation containing SBE6.6-β-CD Lot No. 17CX01.HQ00025 has the highest UV active impurity levels (Max. Abs. = 0.44 AU) and the API supports a total degradation of 1, 42% after 9 weeks. The SBE6.6-β-CD batches that supported two activated carbon treatments were measurably lower in terms of both levels of UV-active impurities and the extent of API degradation. The extent of API degradation that occurred during storage for 9 weeks at 50 ° C correlates with the concentration of UV active impurities present in the formulations. For example, the API formulation containing SBE6.6-β-CD Lot No. 17CX01.HQ00044 (which contains UV active impurities having a Max. Abs. = 0.05 AU) supports a total degradation of only 0.35% after 9 weeks at 50 ° C.

[00296] FIG. 5 provides a graphical representation of the correlation between the initial UV / vis absorption of SBE66-β-CD batches at a wavelength of 245 nm to 270 nm, and the extent of API degradation determined at 4 weeks and 9 weeks. Referring to FIG. 5, the data show that in both 4 weeks and 9 weeks - d -, the extent of API degradation increases with the concentration of UV / vis-absorbing drug degradation impurities present in the SBE66-β-CD composition.

EXAMPLE 16 Measurement of Impurities by Processing

[00297] SBE6.6-β-CD samples after reaction (Example 5), after ultrafiltration (Example 6), after the second carbon column (Example 7), after concentration (Example 8), and as a final product , were separated, identified, and quantified using a Shimadzu Prominence 20A HPLC instrument and a ZIC® pHILIC column (150 x 4.6 mm, 5 μm, 200 A, PEEK Merck SeQuant ™ SN 1479), using a Corona Aerosol Detector ( ESA Bioscience) loaded. A mobile gradient phase method is performed using a 100 mM ammonia-shaped solution (pH adjusted to 4.6), methanol, 2-propanol, and acetonitrile 15/5/20/65 (A), and a solution 30 mM ammonia format (pH adjusted to 4.6), methanol, 2-propanol, and acetonitrile 65/5/20/10 (B). A Captisol® sample solution is prepared at a concentration of approximately 40 mg / mL in HPLC grade acetonitrile / water, and analyzed versus a prepared reference solution of known concentration of 4-hydroxybutane-1-sulfonic acid, disodium bis (4-sulfobutyl) ether, chloride, sodium, phosphate, silicon dioxide, and β-cyclodextrin in acetonitrile / water at the impurity specification limit. Validation studies have shown the method to be specific, linear in the impurity specification range, accurate, and stable. The gradient used is shown in the following table.

[00298] As shown in FIG. 6, after ultrafiltration of the SBE6.6-β-CD crude product, impurities such as β-cyclodextrin and 4-hydroxybutane-l-sulfonic acid (4-HBSA) are present. After a second column with activated carbon, the amount of impurities of β-cyclodextrin and 4-hydroxybutane-l-sulfonic acid was reduced. However, as shown in FIG. 6, there are high amounts of chloride present in the product after the two columns.

EXAMPLE 17 Measurement of Chloride Concentration

[00299] SBE66-β-CD samples after reaction (Example 5), after ultrafiltration (Example 6), after the second carbon column (Example 7), after concentration (Example 8), and as a final product, were analyzed using a loaded Corona Aerosol Detector (ESA Bioscience) to determine chloride concentration.

[00300] As shown in FIG. 7, after ultrafiltration, the residual chloride level drops to approximately zero. After further purification using two columns of activated carbon, chloride is added back into the SBE6.6-β-CD solution.

EXAMPLE 18 Measurement of Chloride Concentration

[00301] SBE66-β-CD samples after reaction (Example 5), after ultrafiltration (Example 6), 5, 10, and 20 minutes after adding to the first column of activated carbon, and 5, 10, and 20 minutes after addition to the second column of activated carbon, were analyzed using a loaded Corona Aerosol Detector (ESA Bioscience) to determine chloride concentration.

[00302] As shown in FIG. 8, the chloride impurity level for two batches of commercial SBE6.6-β-CD is approximately zero after ultrafiltration, and increases substantially after treatment with activated carbon during the first 5 minutes, with the level falling after 10 and 20 minutes.

EXAMPLE 19 Purification of Activated Carbon Using a Dedicated Tank System

[00303] Activated carbon can be added to a dedicated tank system with an agitator and classification system. The activated carbon can be charged, followed by washing with several portions of water at a rate of agitation determined for a specified period of time. After washing with water, the water layer can be removed from the dedicated tank and washed with additional water. After washing with additional water, the conductivity of the eluted water can be determined using ion chromatography (4.0 X 250 mm USP L50 packaging or similar, with mobile phases of 4 mM sodium bicarbonate in methanol / water (1: 9) , a flow rate of 1 mL / min, a sample volume of 20 μL, and an operating time of 10 min), and when the conductivity is below a predetermined level, the carbon can be suspended in water and pumped into carbon housings. The activated carbon would then be ready for addition of the alkylated cyclodextrin solution.

EXAMPLE 20 Purification of SBE6-6-β-CD Using Activated Carbon Having a Determined Conductivity Level

[00304] A column was loaded with 32 kg (about 11-12% by weight (11.8-12% by weight) of the starting quantity of β-cyclodextrin) of granular activated carbon of SHIRASAGIR DC32, and washed thoroughly with water until the wash samples have a conductivity level less than 10 μS, as shown in the Table below. Conductivity was determined using ion chromatography (4.0 X 250 mm USP L50 packaging or similar, with mobile phases of 4 mM sodium bicarbonate in methanol / water (1: 9), a flow rate of 1 mL / min , a sample volume of 20 μL, and an operating time of 10 min, 25 ° C).

[00305] The ratio of SBE6.6-β-CD to activated carbon was about 8.4: 1 to 8.5: 1 (about 8.44: 1). Once washed, the reaction solution was passed (recycled) through the carbon for at least 2 hours to complete a first treatment cycle.

[00306] A second column was loaded with 32 kg (about 1112%) by weight of the starting amount of granular activated carbon β-cyclodextrin) SHIRASAGIR DC32, and rinsed thoroughly with water until the wash samples have a level of conductivity less than 10 μS (measured by ion chromatography (4.0 X 250 mm USP packaging L50 or similar with mobile phases of 4 mM sodium bicarbonate in methanol / water (1: 9), a flow rate of 1 mL / min, a sample volume of 20 μL, and an operating time of 10 min, 25 ° C)), as shown in the following Table. Once washed, the reaction solution was passed through carbon for at least 2 hours to complete a second treatment cycle.

[00307] After the second treatment cycle, the SBE6.6-β-CD was analyzed using a loaded Corona Aerosol Detector (ESA Bioscience) to determine the chloride concentration.

[00308] As shown in the Table, all of the samples have a chloride content of 0.07% or less, with 6 of the 9 samples having a chloride content of less than 0.05% (the detection limit for chromatography ion). This is an improvement over the measurements using the previous method shown in FIG. 10 which has only a 65% success rate (44 out of 68 samples) in obtaining a chloride level of less than 0.10%. This is also a significant improvement over the previous method for samples of what had passed through two cycles of activated carbon treatment, as shown in FIG. 10, which has only a 48% success rate (20 out of 42 samples) in obtaining chloride levels of less than 0.1%.

EXAMPLE 21 Purification of Activated Carbon at a Constant Conductivity Level

[00309] A column can be loaded with 32 kg (about 11-12% by weight (11.8-12% by weight) of the starting amount of alkylated cyclodextrin) of granular activated carbon SHIRASAGIR DC32, and washed thoroughly with water until the wash samples have a constant conductivity. Following water washes, a portion of an alkylated cyclodextrin solution can be added to the housing, and passed through the carbon for a specified period of time before discharge. An additional alkylated cyclodextrin solution can be added to the housing and passed through the carbon for at least 2 hours, to complete the first treatment cycle.

[00310] A second column can be loaded with 32 kg (about 11-12% by weight (11.8-12% by weight) of the starting amount of alkylated cyclodextrin) of granular activated carbon of SHIRASAGIR DC32, and washed completely with water until the washed samples have a constant conductivity. Following water washes, a portion of an alkylated cyclodextrin solution can be added to the housing, and passed through the carbon for a specified period of time before discharge. An additional alkylated cyclodextrin solution can be added to the housing, and passed through carbon for at least 2 hours, to complete the first treatment cycle.

EXAMPLE 22 Purification of Activated Carbon Using a Washing and Dipping Process

[00311] A first column and a second column were loaded with * kg (about *% by weight (*% by weight) of the starting amount of SHIRASAGIR DC32 granulated activated carbon) filled with purified water in a counter-direction -flow (bottom to top), and allowed to settle. After 30 minutes, the water was discharged from the columns. The first column and the second column were filled for the second time with purified water in a counter-current direction (bottom to top), and allowed to settle. After 30 minutes, the water was discharged from the columns. The first column and the second column were filled for the third time with purified water in counter-flow (bottom to top), and allowed to settle. After 30 minutes, the water was discharged from the columns.

[00312] Then, the first column and second column were filled with purified water in a counter-current direction, and allowed to settle. After 4 hours, the purified water was passed over the columns in a counter-current direction with a flow of about 100 liters / hour in the first column, and about 300 liters / hour in the second column for 3 hours.

[00313] Then, the purified water was passed in a co-current direction through the first column and the second column. After about 1,000 liters of purified water, the conductivity of the water was tested. If the measured conductivity was less than 10 μS / cm, the washing process was considered complete.

[00314] If the measured conductivity was greater than 10 μS / cm, additional washing procedures were followed. First, the water was discharged from the first column and the second column. Then, the first column and the second column were filled with purified water in a counter-current direction, and allowed to settle. After 2 hours, the purified water was passed over the columns in a counter-current direction with a flow of about 100 liters / hour in the first column, and about 300 liters / hour in the second column for 2 hours. Then, the purified water was passed in a co-current direction through the first column and the second column. After about 1,000 liters of purified water, the conductivity of the water was tested. If the measured conductivity was less than 10 μS / cm, the washing process was considered complete. If the measured conductivity was greater than 10μS / cm, the steps in this paragraph were repeated until the measured conductivity was less than 10 μS / cm.

CONCLUSION

[00315] These examples illustrate possible embodiments of the present invention. While various embodiments of the present invention have been described herein, it should be understood that they were presented by way of example only, and not by way of limitation. It will be apparent to those skilled in the art that various changes in form and detail can be made in it without escaping the spirit and scope of the invention. Accordingly, the breadth and scope of the present invention should not be limited by any of the exemplary embodiments described above, but should be defined only in accordance with the following claims and their equivalents.

[00316] It is to be appreciated that the Detailed Description section, and not the Summary and Summary sections, is intended to be used to interpret the claims. The Summary and Summary sections may include one or more, but not all exemplary embodiments of the present invention, as contemplated by the inventor (s), and are therefore not intended to limit the present invention and the claims that follow anyway.

[00317] All of the various aspects, embodiments, and options described here can be combined in any and all variations.

[00318] All documents cited herein, including newspaper articles or abstracts, published, or corresponding foreign or US patent applications, published, or foreign patents, or any other documents, are each fully incorporated by reference here, including all data , tables, figures, and text presented in the mentioned documents.

Claims (46)

1. Process for the preparation of an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, the process being characterized by the fact that it comprises: (a) mixing a cyclodextrin with an alkylating agent to form a reaction medium comprising an alkylated cyclodextrin, one or more unwanted components, and one or more drug-degrading impurities; (b) conducting one or more separations to remove one or more unwanted components from the reaction medium to form a partially purified solution comprising the alkylated cyclodextrin and one or more drug degradation impurities, in which the one or more separations they are ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, or dialysis; (c) preparing a phosphate-free activated carbon having a residual conductivity of 10 μS or less, by a process comprising subjecting the activated carbon to a first carbon washing process comprising adding water, immersing the carbon in water, and draining the carbon. Water; and (d) treating the partially purified solution with phosphate-free activated carbon having a residual conductivity of 10 μS or less, and production of the alkylated cyclodextrin, wherein the alkylated cyclodextrin composition has an absorption of less than 0.5 A.U. due to a drug-degrading agent, as determined by UV / vis spectrophotometry, at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution in a cell having a trajectory length of 1 cm. 2. Process according to claim 1, characterized by the fact that the first carbon washing process comprises immersing the carbon in water for at least 20 minutes. 3. Process according to claim 2, characterized by the fact that the first carbon washing process comprises immersing the carbon in water for about 30 minutes. Process according to any one of claims 1 to 3, characterized in that the first carbon washing process comprises adding water in a countercurrent direction. Process according to any one of claims 1 to 4, characterized by the fact that it further comprises repeating the first carbon washing process at least twice. Process according to any one of claims 1 to 5, characterized by the fact that it further comprises, after the first carbon washing process, a second carbon washing process comprising flow of water over the carbon in a co-direction -chain. 7. Process according to claim 6, characterized by the fact that the second carbon washing process comprises flow of water over the carbon in a co-current direction for at least 1 hour. 8. Process according to claim 6, characterized by the fact that the second carbon washing process comprises flow of water over the carbon in a co-current direction for about 3 hours. Process according to any one of claims 6 to 8, characterized by the fact that it further comprises testing the residual conductivity of the water after the second carbon washing process and, if the residual conductivity of the water is greater than 10 μS , repeat at least one of the first carbon washing process and the second carbon washing process until the residual conductivity of the water is 10 μS or less. Process according to any one of claims 6 to 9, characterized in that the alkylated cyclodextrin composition comprises less than 0.5% (w / w) of a chloride. Process according to any one of claims 6 to 9, characterized in that the alkylated cyclodextrin composition comprises less than 0.1% (w / w) of a chloride. Process according to any one of claims 6 to 9, characterized in that the alkylated cyclodextrin composition comprises less than 0.05% (w / w) of a chloride. 13. Process for the preparation of at least 9 consecutive batches of an alkylated cyclodextrin composition comprising an alkylated cyclodextrin and less than about 0.05% (w / w) of a chloride, the process being for the preparation of each of the batches, characterized by the fact that it comprises: (a) mixing a cyclodextrin with an alkylating agent to form a reaction medium comprising an alkylated cyclodextrin, one or more unwanted components, and one or more drug-degrading impurities; (b) conducting one or more separations to remove the one or more unwanted components from the reaction medium to form a partially purified solution comprising the alkylated cyclodextrin and one or more drug degradation impurities, in which one or more separations they are ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, or dialysis; and (c) treating the partially purified solution with a phosphate-free activated carbon having a residual conductivity of 10 μS or less, and production of the alkylated cyclodextrin, wherein the alkylated cyclodextrin composition has an absorption of less than 0.5 A.U. due to a drug-degrading agent, as determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution in a cell having a length trajectory of 1 cm. 14. Process according to claim 13, characterized by the fact that at least 15 consecutive batches are prepared. 15. Process according to claim 13, characterized by the fact that at least 20 consecutive batches are prepared. 16. Process according to claim 13, characterized by the fact that at least 30 consecutive batches are prepared. 17. Process according to any of claims 13 to 16, characterized by the fact that consecutive batches are prepared within a period of 10 years. 18. Process according to any one of claims 13 to 16, characterized by the fact that consecutive batches are prepared within a period of 5 years. 19. Process according to any of claims 13 to 16, characterized by the fact that consecutive batches are prepared within a period of 3 years. 20. Process according to any one of claims 1 to 19, characterized in that the alkylated cyclodextrin composition additionally comprises less than 500 ppm of a phosphate. 21. Process according to any one of claims 1 to 19, characterized in that the alkylated cyclodextrin composition additionally comprises less than 125 ppm of a phosphate. 22. Process according to any one of claims 1 to 21, characterized by the fact that the residual conductivity is 9 μS, or less. 23. Process according to any one of claims 1 to 21, characterized by the fact that the residual conductivity is 8 μS, or less. 24. Process according to any one of claims 1 to 23, characterized in that the alkylated cyclodextrin composition comprises less than 0.01% (w / w) of a chloride. 25. Process according to any one of claims 1 to 23, characterized in that the alkylated cyclodextrin composition comprises less than 0.005% (w / w) of a chloride. 26. Process according to any one of claims 1 to 23, characterized in that the alkylated cyclodextrin composition comprises less than 0.0001% (w / w) of a chloride. 27. Process according to any one of claims 1 to 26, characterized in that the alkylated cyclodextrin composition has an average degree of substitution of 2 to 9. 28. Process according to any one of claims 1 to 26, characterized in that the alkylated cyclodextrin composition has an average degree of substitution of 4.5 to 7.5. 29. Process according to any one of claims 1 to 26, characterized in that the alkylated cyclodextrin composition has an average degree of substitution of 6 to 7.5. 30. Process according to any one of claims 1 to 29, characterized in that the alkylated cyclodextrin composition has an absorption of less than 0.2 AU, as determined by UV / vis spectrophotometry at a wavelength from 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution in a cell having a path length of 1 cm. 31. Process according to claim 30, characterized by the fact that the absorption is due to a drug-degrading agent. 32. Process according to claim 30 or 31, characterized in that the absorption is determined by UV / vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 500 mg of the cyclodextrin composition alkylated per ml of solution in a cell having a path length of 1 cm. 33. Process according to any of claims 1 to 32, characterized in that the alkylated cyclodextrin composition has an absorption of less than 1 AU, as determined by UV / vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution in a cell having a path length of 1 cm. 34. Process according to any of claims 1 to 32, characterized in that the alkylated cyclodextrin composition has an absorption of less than 0.5 AU, as determined by UV / vis spectrophotometry at a wavelength from 320 nm to 350 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per ml of solution in a cell having a path length of 1 cm. 35. Process according to claim 33 or 34, characterized by the fact that the absorption is due to a color forming agent. 36. Process according to any one of claims 33 to 35, characterized in that the absorption is determined by UV / vis spectrophotometry at a wavelength of 320 nm to 350 nm for an aqueous solution containing 500 mg of the composition of alkylated cyclodextrin per ml of solution in a cell having a path length of 1 cm. 37. Process according to any one of claims 1 to 36, characterized in that the phosphate-free activated carbon is washed with a solvent until the eluted solvent reaches residual conductivity. 38. Process according to any one of claims 1 to 36, characterized by the fact that the phosphate-free activated carbon is washed with water until the eluted water reaches residual conductivity. 39. Process according to any one of claims 1 to 38, characterized by the fact that the alkylated cyclodextrin is a sulfoalkyl ether cyclodextrin of Formula (II):

in which p is 4, 5, or 6, and R1 is independently selected for each occurrence of -OH or -O- (C2-C6 alkylene) -S03 - T, in which T is independently selected for each occurrence of pharmaceutically cations acceptable, provided that at least one R1 is -OH, and at least one R1 is O- (C2-C6 alkylene) -S03 - T. 40. Process according to claim 39, characterized by the fact that R1 is independently selected in each occurrence of -OH or -O- (C4 alkylene) -SO3 - T, and -T is Na + in each occurrence. 41. Process according to claim 39 or 40, characterized by the fact that sulfoaquil cyclodextrin ether (SAE-CD) is a sulfobutyl cyclodextrin ether (SBE-CD). 42. Process according to any one of claims 1 to 38, characterized by the fact that the alkylated cyclodextrin is a hydroxyalkyl ether cyclodextrin (HAE-CD). 43. The process, according to claim 42, characterized by the fact that HAE-CD is a hydroxypropyl ether cyclodextrin (HPE-CD). 44. Process according to any one of claims 1 to 43, characterized by the fact that it further comprises combining the alkylated cyclodextrin composition with one or more excipients. 45. Process according to any one of claims 1 to 44, characterized in that it further comprises combining the alkylated cyclodextrin composition with an active agent. 46. Process for the preparation of a pharmaceutical composition, characterized by the fact that it comprises: preparing an alkylated cyclodextrin according to the process as defined in any one of claims 1 to 45; and combining the alkylated cyclodextrin with carfilzomib.

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